Methods of treating neuroepithelial tumors using selective glucocorticoid receptor modulators

ABSTRACT

Applicant discloses methods for treating a glucocorticoid receptor positive (GR+) neuroepithelial tumor in a subject, comprising administering a selective glucocorticoid receptor modulator (SGRM) in an amount effective to reduce the tumor load in a subject. The GR+ neuroepithelial tumor may be a neurofibromatosis type 2 (NF 2) tumor; the GR+ neuroepithelial tumor may be a schwannoma, meningioma, or ependymoma. In embodiments, the GR+ neuroepithelial tumor is not an adrenocorticotropic hormone (ACTH)-secreting tumor. In embodiments, the SGRM comprises a steroidal backbone. In embodiments, the SGRM is mifepristone. In embodiments, the SGRM comprises a non-steroidal backbone, such as, e.g., a cyclohexyl pyrimidine, a fused azadecalin, a heteroaryl ketone fused azadecalin, or an octahydro fused azadecalin backbone. The SGRM may be administered orally. The SGRM may be administered alone. In embodiments, the SGRM is administered with at least one non-SGRM therapy, e.g., a chemotherapy, a radiation therapy, or other therapeutic agents.

BACKGROUND

Meningioma, schwannoma and ependymoma are neuroepithelial tumorsfrequently seen in patients with neurofibromatosis type 2 (“NF 2”).Meningioma accounts for about 36.1% of all primary brain tumors.Meningioma arises from meninges, the three thin layers of tissuecovering the brain and spinal cord, and are often found near the top andthe outer curve of the brain and at the base of the skull. Schwannomaaccounts for about 8% of all primary brain tumors. Schwannoma is a nervesheath tumor composed of Schwann cells. The tumor cells always stay onthe outside of the nerve, but the tumor itself may either push the nerveaside and/or up against a bony structure. Both the incidence ofmeningioma and that of schwannoma increases with age and occur abouttwice as often in women as in men. Ependymoma accounts for about 5% ofadult intracranial gliomas and up to 10% of childhood tumors of thecentral nervous system (CNS). Ependymomas develop from cells that lineboth the hollow cavities of the brain and the canal containing thespinal cord, but they usually arise from the floor of the fourthventricle, situated in the lower back portion of the brain.

Conventional treatment options for neuroepithelial tumors such asmeningioma, schwannoma, and ependymoma include surgery, radiationtherapy, and chemotherapy. Surgery is currently the primary treatmentoption for patients having meningioma, schwannoma, or ependymoma.However, surgery often cannot completely remove tumors and may not bepossible if the tumor has spread or it cannot be removed withoutdamaging the brain. Radiation therapy and chemotherapy, taking advantageof the fact that cancer cells in general have higher proliferativecapacity and are more sensitive to DNA damage, kills tumor cells byinflicting a generalized damage to DNA and destabilization ofchromosomal structure, which eventually leads to destruction of cancercells. Non-limiting examples of radiation therapies include γ-rays andx-rays and non-limiting examples of chemotherapy agents includebleomycin, cis-platin, vinblastine, cyclophosphamide, 5′-fluorouracil,and methotrexate. These treatments are particularly effective for thosetypes of cancers that have defects in cell cycle checkpoint, whichlimits the ability of these cells to repair damaged DNA beforeundergoing cell division. The non-selective nature of these treatments,however, often results in severe and debilitating side effects. Thesystemic use of these drugs may result in damage to normally healthyorgans and tissues and compromise the long-term health of the patient.Thus, there is a need for novel therapeutic options for treatingneuroepithelial tumors, such as, e.g., meningioma, schwannoma, andependymoma, and the present methods disclosed below meet these and otherneeds.

SUMMARY

Disclosed herein are methods for treating a GR⁺ neuroepithelial tumor ina subject (where “GR⁺” means that the tumor expresses the glucocorticoidreceptor (GR)), the methods comprising administering to the subject aglucocorticoid receptor modulator (GRM), such as a selectiveglucocorticoid receptor modulator (SGRM), in an amount effective toreduce the tumor load of the GR⁺ neuroepithelial tumor in the subjectwith the proviso that the subject not be otherwise suffering from adisorder treatable with a SGRM. Non-limiting examples of disorders wheretreatment comprising administering SGRMs are indicated as beneficialinclude Cushing's syndrome, psychiatric disorders such as psychoticmajor depression, cocaine addition, stress disorders, postpartumpsychosis, and cancers treatable with combinations of taxanes and SGRMs(e.g., breast and prostate). In embodiments of the methods disclosedherein, the GR⁺ neuroepithelial tumor is not an adrenocorticotropichormone (ACTH)-secreting tumor. In some embodiments, the GR⁺neuroepithelial tumor is neurofibromatosis type 2 (NF 2). In someembodiments, the GR⁺ neuroepithelial tumor is a tumor selected fromschwannoma, meningioma, and ependymoma.

In some cases, the SGRM is orally administered. In some cases, the SGRMis administered by transdermal application, by a nebulized suspension,or by an aerosol spray. In some cases, the SGRM is a nonsteroidalglucocorticoid receptor modulator. In some cases, the nonsteroidalglucocorticoid receptor modulator is orally administered. In some cases,the nonsteroidal glucocorticoid receptor modulator is administered bytransdermal application, by a nebulized suspension, or by an aerosolspray. In some cases, the SGRM is administered to the subject for atleast two weeks. In some cases, the SGRM is administered to the subjectfor at least three weeks, or four weeks, or two months, or three months,or longer.

In some cases, the effective amount of the SGRM is a daily dose ofbetween 1 and 100 mg/kg/day, wherein the SGRM is administered alone orwith at least one non-SGRM therapy, e.g., a chemotherapy, a radiationtherapy, or other therapeutic agents. In some embodiments, the dailydose is 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 30, 40, 50 60, 70, 80, 90or 100 mg/kg/day. In some cases, the nonsteroidal glucocorticoidreceptor modulator is administrated for at least 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50,55, 60, 65, 70, 75, or 80 weeks.

In some embodiments, the glucocorticoid receptor modulator, such as aSGRM, comprises a steroidal backbone with at least one phenyl-containingmoiety in the 11-β position of the steroidal backbone. In some cases,the phenyl-containing moiety in the 11-β position of the steroidalbackbone is a dimethylaminophenyl moiety. In some cases, theglucocorticoid receptor modulator is mifepristone. In some embodiments,the glucocorticoid receptor modulator is selected from the groupconsisting of11β-(4-dimethylaminoethoxyphenyl)-17α-propynyl-17β-hydroxy-4,9estradien-3-one and(17α)-17-hydroxy-19-(4-methylphenyl)androsta-4,9(11)-dien-3-one. In someembodiments, the glucocorticoid receptor modulator is(11β,17β)-11-(1,3-benzodioxol-5-yl)-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one.

In some embodiments, the glucocorticoid receptor modulator, such as aSGRM, has a non-steroidal backbone. In some cases, the glucocorticoidreceptor modulator backbone is a cyclohexyl pyrimidine. In some cases,wherein the cyclohexyl pyrimidine has the following formula:

wherein the dashed line is absent or a bond; X is selected from thegroup consisting of O and S; R¹ is selected from the group consisting ofcycloalkyl, heterocycloalkyl, aryl and heteroaryl, optionallysubstituted with from 1 to 3 R^(1a) groups; each R^(1a) is independentlyselected from the group consisting of H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkyl OR^(1b), halogen, C₁₋₆ haloalkyl, C₁₋₆haloaloxy, OR^(1b), NR^(1b)R^(1c), C(O)R^(1b), C(O)OR^(1b), OC(O)R^(1b),C(O)NR^(1b)R^(1c), NR^(1b)C(O)R^(1c), SO₂R^(1b), SO₂NR^(1b)R^(1c),cycloalkyl, heterocycloalkyl, aryl and heteroaryl; R^(1b) and R^(1c) areeach independently selected from the group consisting of H and C₁₋₆alkyl; R² is selected from the group consisting of H, C₁₋₆ alkyl, C₁₋₆alkyl-OR^(1b), C₁₋₆ alkyl NR^(1b)R^(1c) and C₁₋₆ alkyleneheterocycloalkyl; R³ is selected from the group consisting of H and C₁₋₆alkyl; Ar is aryl, optionally substituted with 1-4 R⁴ groups; each R⁴ isindependently selected from the group consisting of H, C₁₋₆ alkyl, C₁₋₆alkoxy, halogen, C₁₋₆ haloalkyl and C₁₋₆ haloalkoxy; L¹ is a bond orC₁₋₆ alkylene; and subscript n is an integer from 0 to 3, or salts andisomers thereof.

In some cases, the glucocorticoid receptor modulator backbone is a fusedazadecalin. In some cases, the fused azadecalin is a compound having thefollowing formula:

wherein L¹ and L² are members independently selected from a bond andunsubstituted alkylene; R¹ is a member selected from unsubstitutedalkyl, unsubstituted heteroalkyl, unsubstituted heterocycloalkyl,—OR^(1A), NR^(1C)R^(1D), —C(O)NR^(1C)R^(1D), and —C(O)OR^(1A), whereinR^(1A) is a member selected from hydrogen, unsubstituted alkyl andunsubstituted heteroalkyl, R^(1C) and R^(1D) are members independentlyselected from unsubstituted alkyl and unsubstituted heteroalkyl, whereinR^(1C) and R^(1D) are optionally joined to form an unsubstituted ringwith the nitrogen to which they are attached, wherein said ringoptionally comprises an additional ring nitrogen; R² has the formula:

wherein R^(2G) is a member selected from hydrogen, halogen,unsubstituted alkyl, unsubstituted heteroalkyl, unsubstitutedcycloalkyl, unsubstituted heterocycloalkyl, —CN, and —CF₃; J is phenyl;t is an integer from 0 to 5; X is —S(O₂)—; and R⁵ is phenyl optionallysubstituted with 1-5 R^(5A) groups, wherein R^(5A) is a member selectedfrom hydrogen, halogen, —OR^(5A1), S(O₂)NR^(5A2)R^(5A3), —CN, andunsubstituted alkyl, wherein R^(5A1) is a member selected from hydrogenand unsubstituted alkyl, and R^(5A2) and R^(5A3) are membersindependently selected from hydrogen and unsubstituted alkyl, or saltsand isomers thereof.

In some cases, the glucocorticoid receptor modulator backbone is aheteroaryl ketone fused azadecalin or an octahydro fused azadecalin. Insome cases, the heteroaryl ketone fused azadecalin has the formula:

wherein R¹ is a heteroaryl ring having from 5 to 6 ring members and from1 to 4 heteroatoms each independently selected from the group consistingof N, O and S, optionally substituted with 1-4 groups each independentlyselected from R^(1a); each R^(1a) is independently selected from thegroup consisting of hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, CN, N-oxide, C₃₋₈ cycloalkyl, and C₃₋₈heterocycloalkyl; ring J is selected from the group consisting of acycloalkyl ring, a heterocycloalkyl ring, an aryl ring and a heteroarylring, wherein the heterocycloalkyl and heteroaryl rings have from 5 to 6ring members and from 1 to 4 heteroatoms each independently selectedfrom the group consisting of N, O and S; each R² is independentlyselected from the group consisting of hydrogen, C₁₋₆ alkyl, halogen,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkyl-C₁₋₆ alkoxy,CN, OH, NR^(2a)R^(2b), C(O)R^(2a), C(O)OR^(2a), C(O)NR^(2a)R^(2b),SR^(2a), S(O)R^(2a), S(O)₂R^(2a), C₃₋₈ cycloalkyl, and C₃₋₈heterocycloalkyl, wherein the heterocycloalkyl groups are optionallysubstituted with 1-4 R^(2c) groups; alternatively, two R² groups linkedto the same carbon are combined to form an oxo group (═O);alternatively, two R² groups are combined to form a heterocycloalkylring having from 5 to 6 ring members and from 1 to 3 heteroatoms eachindependently selected from the group consisting of N, O and S, whereinthe heterocycloalkyl ring is optionally substituted with from 1 to 3R^(2d) groups; R^(2a) and R^(2b) are each independently selected fromthe group consisting of hydrogen and C₁₋₆ alkyl; each R^(2c) isindependently selected from the group consisting of hydrogen, halogen,hydroxy, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, CN, and NR^(2a)R^(2b); eachR^(2d) is independently selected from the group consisting of hydrogenand C₁₋₆ alkyl, or two R^(2d) groups attached to the same ring atom arecombined to form (═O); R³ is selected from the group consisting ofphenyl and pyridyl, each optionally substituted with 1-4 R^(3a) groups;each R^(3a) is independently selected from the group consisting ofhydrogen, halogen, and C₁₋₆ haloalkyl; and subscript n is an integerfrom 0 to 3; or salts and isomers thereof.

In some cases, the octahydro fused azadecalin has the formula:

wherein R¹ is a heteroaryl ring having from 5 to 6 ring members and from1 to 4 heteroatoms each independently selected from the group consistingof N, O and S, optionally substituted with 1-4 groups each independentlyselected from R^(1a); each R^(1a) is independently selected from thegroup consisting of hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, N-oxide, and C₃₋₈ cycloalkyl; ring J isselected from the group consisting of an aryl ring and a heteroaryl ringhaving from 5 to 6 ring members and from 1 to 4 heteroatoms eachindependently selected from the group consisting of N, O and S; each R²is independently selected from the group consisting of hydrogen, C₁₋₆alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆alkyl-C₁₋₆ alkoxy, CN, OH, NR^(2a)R^(2b), C(O)R^(2a), C(O)OR^(2a),C(O)NR^(2a)R^(2b), SR^(2a), S(O)R^(2a), S(O)₂R^(2a), C₃₋₈ cycloalkyl,and C₃₋₈ heterocycloalkyl having from 1 to 3 heteroatoms eachindependently selected from the group consisting of N, O and S;alternatively, two R² groups on adjacent ring atoms are combined to forma heterocycloalkyl ring having from 5 to 6 ring members and from 1 to 3heteroatoms each independently selected from the group consisting of N,O and S, wherein the heterocycloalkyl ring is optionally substitutedwith from 1 to 3 R^(2c) groups; R^(2a), R^(2b) and R^(2c) are eachindependently selected from the group consisting of hydrogen and C₁₋₆alkyl; each R^(3a) is independently halogen; and subscript n is aninteger from 0 to 3, or salts and isomers thereof.

In some cases, the SGRM is CORT125134, i.e.,(R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,which has the following structure:

In some cases, the SGRM is CORT125281, i.e.,((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,which has the following structure:

DETAILED DESCRIPTION A. Introduction

This method disclosed herein can be used to treat a patient hosting aneuroepithelial tumors such as, e.g., a meningioma, a schwannoma, or anependymoma, by administering at an effective amount of SGRM alone or incombination with other therapies.

B. Definitions

As used herein, the term “subject” or “patient” refers to a human ornon-human organism. Thus, the methods and compositions described hereinare applicable to both human and veterinary disease. In certainembodiments, subjects are “patients,” i.e., living humans that arereceiving medical care for a disease or condition. This includes personswith no defined illness who are being investigated for signs ofpathology. Preferred are subjects who have an existing diagnosis of aparticular cancer which is being targeted by the compositions andmethods disclosed herein. In some cases, a subject may suffer from oneor more types of cancer simultaneously, at least one of which istargeted by the compositions and methods disclosed herein. Preferredcancers for treatment with the compositions described herein include,but are not limited to neuroepithelial tumors, such as meningioma,schwannoma, and ependymoma.

As used herein, the term “tumor load” or “tumor burden” generally refersto the number of cancer cells, the size of a tumor, or the amount ofcancer in the body in a subject at any given time. Tumor load can bedetected by e.g., measuring the expression of tumor specific geneticmarkers and measuring tumor size by a number of well-known, biochemicalor imaging methods disclosed herein, infra.

As used herein, the term “effective amount” or “therapeutic amount”refers to an amount of a pharmacological agent effective to treat,eliminate, or mitigate at least one symptom of the disease beingtreated. In some cases, “therapeutically effective amount” or “effectiveamount” can refer to an amount of a functional agent or of apharmaceutical composition useful for exhibiting a detectabletherapeutic or inhibitory effect. The effect can be detected by anyassay method known in the art. The effective amount can be an amounteffective to invoke an antitumor response. The effective amount can bean amount effective to evoke a humoral and/or cellular immune responsein the recipient subject leading to growth inhibition or death of targetcells. For the purpose of this disclosure, the therapeutic amount ofSGRM is an amount that would reduce tumor load or bring about otherdesired beneficial clinical outcomes related to cancer improvement whenused alone or with other therapies.

As used herein, the terms “administer,” “administering,” “administered”or “administration” refer to providing a compound or a composition(e.g., one described herein), to a subject or patient.

As used herein, the term “compound” is used to denote a molecular moietyof unique, identifiable chemical structure. A molecular moiety(“compound”) may exist in a free species form, in which it is notassociated with other molecules. A compound may also exist as part of alarger aggregate, in which it is associated with other molecule(s), butnevertheless retains its chemical identity. A solvate, in which themolecular moiety of defined chemical structure (“compound”) isassociated with a molecule(s) of a solvent, is an example of such anassociated form. A hydrate is a solvate in which the associated solventis water. The recitation of a “compound” refers to the molecular moietyitself (of the recited structure), regardless whether it exists in afree form or an associated form.

As used herein, the term “pharmaceutically acceptable carrier” isintended to include any and all solvents, dispersion media, coatings,antibacterial and antifungal agents, isotonic and absorption delayingagents, and the like, compatible with pharmaceutical administration. Theuse of such media and agents for pharmaceutically active substances iswell known in the art. Except insofar as any conventional media or agentis incompatible with the active compound, use thereof in thecompositions is contemplated. Supplementary active compounds can also beincorporated into the compositions.

As used herein, the term “mineralocorticoid receptor” (MR) refers totype I glucocorticoid receptor, that binds mineralocorticoids. The MRbinds aldosterone, and is also referred to as the “aldosteronereceptor”.

As used herein, the term “Glucocorticoid receptor” (“GR”) refers to thetype II glucocorticoid receptor (“type II” of the family ofintracellular receptors which specifically bind to cortisol and/orcortisol analogs such as dexamethasone (See, e.g., Turner & Muller, J.Mol. Endocrinol. Oct. 1, 2005 35 283-292)). The GR is also referred toas the cortisol receptor. The term GR includes isoforms of GR,recombinant GR and mutated GR. A cell, tissue, organ, tumor, or otheranimal portion or material that expresses GR is termed GR “positive”(GR⁺).

The term “Glucocorticoid receptor modulator” and its acronym “GRM”, alsoknown and described in the scientific and patent literature as, e.g.,either a glucocorticoid receptor agonist or a glucocorticoid receptorantagonist, refers to any compound which alters, e.g., inhibits anybiological response associated with the binding of GR to an agonist. Forexample, a GR agonist, such as dexamethasone, increases the activity oftyrosine aminotransferase (TAT) in HepG2 cells (a human liverhepatocellular carcinoma cell line; ECACC, UK). Accordingly, GRMs asdiscussed herein can be identified by measuring the ability of thecompound to inhibit the effect of dexamethasone. TAT activity can bemeasured as outlined in the literature by A. Ali et al., J. Med. Chem.,2004, 47, 2441-2452. A modulator is a compound with an IC₅₀ (halfmaximal inhibition concentration) of less than 10 micromolar. SeeExample 1, infra.

As used herein, the term “selective glucocorticoid receptor modulator”and its acronym “SGRM” refer to any composition or compound whichalters, e.g., inhibits any biological response associated with thebinding of a GR to an agonist. By “selective,” the drug preferentiallybinds to the GR rather than other nuclear receptors, such as theprogesterone receptor (PR), the mineralocorticoid receptor (MR) or theandrogen receptor (AR). It is preferred that the selectiveglucocorticoid receptor modulator bind GR with an affinity that is 10×greater ( 1/10^(th) the K_(d) value) than its affinity to the MR, AR, orPR, both the MR and PR, both the MR and AR, both the AR and PR, or tothe MR, AR, and PR. In a more preferred embodiment, the selectiveglucocorticoid receptor modulator (SGRM) binds GR with an affinity thatis 100× greater ( 1/100^(th) the K_(d) value) than its affinity to theMR, AR, or PR, both the MR and PR, both the MR and AR, both the AR andPR, or to the MR, AR, and PR. In another embodiment, the selectiveglucocorticoid receptor modulator binds GR with an affinity that is1000× greater ( 1/1000^(th) the K_(d) value) than its affinity to theMR, AR, or PR, both the MR and PR, both the MR and AR, both the AR andPR, or to the MR, AR, and PR.

As used herein, the terms “antiglucocorticoid” and “antiglucocorticoidactivity” refer to compounds, and the actions of such compounds, whichoppose, reduce, or prevent one or more of: the binding of glucocorticoidreceptor ligands to GR, the activation of GR, the expression of GR,levels of glucocorticoid ligands, or otherwise modulate GR so as toreduce or abolish GR action or activity.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients such as the said compounds,their tautomeric forms, their derivatives, their analogues, theirstereoisomers, their polymorphs, their pharmaceutically acceptablesalts, esters, ethers, metabolites, mixtures of isomers, theirpharmaceutically acceptable solvates and pharmaceutically acceptablecompositions in specified amounts, as well as any product which results,directly or indirectly, from combination of the specified ingredients inthe specified amounts. Such term in relation to a pharmaceuticalcomposition is intended to encompass a product comprising the activeingredient(s), and the inert ingredient(s) that make up the carrier, aswell as any product which results, directly or indirectly, incombination, complexation or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients. Accordingly, the pharmaceutical compositions disclosedherein are meant to encompass any composition made by admixing compoundsdiscussed herein and their pharmaceutically acceptable carriers.

In some embodiments, the term “consisting essentially of” refers to acomposition in a formulation whose only active ingredient is theindicated active ingredient, however, other compounds may be includedwhich are for stabilizing, preserving, etc. the formulation, but are notinvolved directly in the therapeutic effect of the indicated activeingredient. In some embodiments, the term “consisting essentially of”can refer to compositions which contain the active ingredient andcomponents which facilitate the release of the active ingredient. Forexample, the composition can contain one or more components that provideextended release of the active ingredient over time to the subject. Insome embodiments, the term “consisting” refers to a composition, whichcontains the active ingredient and a pharmaceutically acceptable carrieror excipient.

The term “steroidal backbone” in the context of glucocorticoid receptorantagonists containing such refers to glucocorticoid receptorantagonists that contain modifications of the basic structure ofcortisol, an endogenous steroidal glucocorticoid receptor ligand. Thebasic structure of a steroidal backbone is provided as Formula I:

The two most commonly known classes of structural modifications of thecortisol steroid backbone to create glucocorticoid antagonists includemodifications of the 11-β hydroxy group and modification of the 17-βside chain (See, e. g., Lefebvre (1989) J. Steroid Biochem. 33:557-563).

As used herein, the phrase “non-steroidal backbone” in the context ofSGRMs refers to SGRMs that do not share structural homology to, or arenot modifications of, cortisol with its steroid backbone containingseventeen carbon atoms, bonded in four fused rings. Such compoundsinclude synthetic mimetics and analogs of proteins, including partiallypeptidic, pseudopeptidic and non-peptidic molecular entities.

Non-steroidal GRMs, such as SGRM compounds, include GRMs having a fusedazadecalin backbone, a heteroaryl ketone fused azadecalin backbone, andan octahydro fused azadecalin backbone. Exemplary GRMs having a fusedazadecalin backbone include those described in U.S. Pat. Nos. 7,928,237and 8,461,172. Exemplary SGRMs having a heteroaryl ketone fusedazadecalin backbone include those described in U.S. 2014/0038926, nowU.S. Pat. No. 8,859,774. Exemplary GRMs having an octohydro fusedazadecalin backbone include those described in U.S. Patent Appl.Publication No. 2015/0148341, entitled Octahydro Fused AzadecalinGlucocorticoid Receptor Modulators.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

“Alkyl” refers to a straight or branched, saturated, aliphatic radicalhaving the number of carbon atoms indicated. Alkyl can include anynumber of carbons, such as C₁₋₂, C₁₋₃, C₁₋₄, C₁₋₅, C₁₋₆, C₁₋₇, C₁₋₈,C₁₋₉, C₁₋₁₀, C₂₋₃, C₂₋₄, C₂₋₅, C₂₋₆, C₃₋₄, C₃₋₅, C₃₋₆, C₄₋₅, C₄₋₆, andC₅₋₆. For example, C₁₋₆ alkyl includes, but is not limited to, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec.butyl, tert.butyl,pentyl, isopentyl, and hexyl.

“Alkoxy” refers to an alkyl group having an oxygen atom that connectsthe alkyl group to the point of attachment: alkyl-O—. As for the alkylgroup, alkoxy groups can have any suitable number of carbon atoms, suchas C₁₋₆. Alkoxy groups include, for example, methoxy, ethoxy, propoxy,iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy,pentoxy, hexoxy, etc.

“Halogen” refers to fluorine, chlorine, bromine, and iodine.

“Haloalkyl” refers to alkyl, as defined above, where some or all of thehydrogen atoms are replaced with halogen atoms. As for the alkyl group,haloalkyl groups can have any suitable number of carbon atoms, such asC₁₋₆, and include trifluoromethyl, fluoromethyl, etc.

The term “perfluoro” can be used to define a compound or radical whereall the hydrogens are replaced with fluorine. For example,perfluoromethane includes 1,1,1-trifluoromethyl.

“Haloalkoxy” refers to an alkoxy group where some or all of the hydrogenatoms are substituted with halogen atoms. As for the alkyl group,haloalkoxy groups can have any suitable number of carbon atoms, such asC₁₋₆. The alkoxy groups can be substituted with 1, 2, 3, or morehalogens. When all the hydrogens are replaced with a halogen, forexample by fluorine, the compounds are per-substituted, for example,perfluorinated. Haloalkoxy includes, but is not limited to,trifluoromethoxy, 2,2,2-trifluoroethoxy, and perfluoroethoxy.

“Cycloalkyl” refers to a saturated or partially unsaturated, monocyclic,fused bicyclic, or bridged polycyclic ring assembly containing from 3 to12 ring atoms, or the number of atoms indicated. Cycloalkyl can includeany number of carbons, such as C₃₋₆, C₄₋₆, C₅₋₆, C₃₋₈, C₄₋₈, C₅₋₈, C₆₋₈,C₃₋₉, C₃₋₁₀, C₃₋₁₁, and C₃₋₁₂. Saturated monocyclic cycloalkyl ringsinclude, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl ringsinclude, for example, norbornane, [2.2.2] bicyclooctane,decahydronaphthalene, and adamantane. Cycloalkyl groups can also bepartially unsaturated, having one or more double or triple bonds in thering. Representative cycloalkyl groups that are partially unsaturatedinclude, but are not limited to, cyclobutene, cyclopentene, cyclohexene,cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene,cyclooctene, cyclooctadiene (1,3-, 1,4- and 1,5-isomers), norbornene,and norbornadiene. When cycloalkyl is a saturated monocyclic C₃₋₈cycloalkyl, exemplary groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl. When cycloalkyl is a saturated monocyclic C₃₋₆ cycloalkyl,exemplary groups include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl.

“Heterocycloalkyl” refers to a saturated ring system having from 3 to 12ring members and from 1 to 4 heteroatoms of N, O, and S. Additionalheteroatoms can also be useful, including but not limited to, B, Al, Si,and P. The heteroatoms can also be oxidized, such as, but not limitedto, —S(O)— and —S(O)₂—. Heterocycloalkyl groups can include any numberof ring atoms, such as 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitablenumber of heteroatoms can be included in the heterocycloalkyl groups,such as 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3to 4. The heterocycloalkyl group can include groups such as aziridine,azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine,pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 1,4-isomers),oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane,thiirane, thietane, thiolane (tetrahydrothiophene), thiane(tetrahydrothiopyran), oxazolidine, isoxalidine, thiazolidine,isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine,dioxane, or dithiane. The heterocycloalkyl groups can also be fused toaromatic or non-aromatic ring systems to form members including, but notlimited to, indoline.

When heterocycloalkyl includes 3 to 8 ring members and 1 to 3heteroatoms, representative members include, but are not limited to,pyrrolidine, piperidine, tetrahydrofuran, oxane, tetrahydrothiophene,thiane, pyrazolidine, imidazolidine, piperazine, oxazolidine,isoxazolidine, thiazolidine, isothiazolidine, morpholine,thiomorpholine, dioxane and dithiane. Heterocycloalkyl can also form aring having 5 to 6 ring members and 1 to 2 heteroatoms, withrepresentative members including, but not limited to, pyrrolidine,piperidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine,imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine,isothiazolidine, and morpholine.

“Aryl” refers to an aromatic ring system having any suitable number ofring atoms and any suitable number of rings. Aryl groups can include anysuitable number of ring atoms, such as 6, 7, 8, 9, 10, 11, 12, 13, 14,15, or 16 ring atoms, as well as from 6 to 10, 6 to 12, or 6 to 14 ringmembers. Aryl groups can be monocyclic, fused to form bicyclic ortricyclic groups, or linked by a bond to form a biaryl group.Representative aryl groups include phenyl, naphthyl and biphenyl. Otheraryl groups include benzyl, that has a methylene linking group. Somearyl groups have from 6 to 12 ring members, such as phenyl, naphthyl, orbiphenyl. Other aryl groups have from 6 to 10 ring members, such asphenyl or naphthyl. Some other aryl groups have 6 ring members, such asphenyl. Aryl groups can be substituted or unsubstituted.

“Heteroaryl” refers to a monocyclic, fused bicyclic, or tricyclicaromatic ring assembly containing 5 to 16 ring atoms, where from 1 to 5of the ring atoms are a heteroatom such as N, O, or S. Additionalheteroatoms can also be useful, including but not limited to, B, Al, Si,and P. The heteroatoms can also be oxidized, such as, but not limitedto, N-oxide, —S(O)—, and —S(O)₂—. Heteroaryl groups can include anynumber of ring atoms, such as 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Anysuitable number of heteroatoms can be included in the heteroaryl groups,such as 1, 2, 3, 4, or 5; or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2to 4, 2 to 5, 3 to 4, or 3 to 5. Heteroaryl groups can have from 5 to 8ring members and from 1 to 4 heteroatoms, or from 5 to 8 ring membersand from 1 to 3 heteroatoms, or from 5 to 6 ring members and from 1 to 4heteroatoms, or from 5 to 6 ring members and from 1 to 3 heteroatoms.The heteroaryl group can include groups such as pyrrole, pyridine,imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine,pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiophene,furan, thiazole, isothiazole, oxazole, and isoxazole. The heteroarylgroups can also be fused to aromatic ring systems, such as a phenylring, to form members including, but not limited to, benzopyrroles suchas indole and isoindole, benzopyridines such as quinoline andisoquinoline, benzopyrazine (quinoxaline), benzopyrimidine(quinazoline), benzopyridazines such as phthalazine and cinnoline,benzothiophene, and benzofuran. Other heteroaryl groups includeheteroaryl rings linked by a bond, such as bipyridine. Heteroaryl groupscan be substituted or unsubstituted.

The heteroaryl groups can be linked via any position on the ring. Forexample, pyrrole includes 1-, 2-, and 3-pyrrole; pyridine includes 2-,3- and 4-pyridine; imidazole includes 1-, 2-, 4- and 5-imidazole;pyrazole includes 1-, 3-, 4- and 5-pyrazole; triazole includes 1-, 4-and 5-triazole; tetrazole includes 1- and 5-tetrazole; pyrimidineincludes 2-, 4-, 5- and 6-pyrimidine; pyridazine includes 3- and4-pyridazine; 1,2,3-triazine includes 4- and 5-triazine; 1,2,4-triazineincludes 3-, 5- and 6-triazine; 1,3,5-triazine includes 2-triazine;thiophene includes 2- and 3-thiophene; furan includes 2- and 3-furan;thiazole includes 2-, 4- and 5-thiazole; isothiazole includes 3-, 4- and5-isothiazole; oxazole includes 2-, 4- and 5-oxazole; isoxazole includes3-, 4- and 5-isoxazole; indole includes 1-, 2- and 3-indole; isoindoleincludes 1- and 2-isoindole; quinoline includes 2-, 3- and 4-quinoline;isoquinoline includes 1-, 3- and 4-isoquinoline; quinazoline includes 2-and 4-quinazoline; cinnoline includes 3- and 4-cinnoline; benzothiopheneincludes 2- and 3-benzothiophene; and benzofuran includes 2- and3-benzofuran.

Some heteroaryl groups include those having from 5 to 10 ring membersand from 1 to 3 ring atoms including N, O, or S, such as pyrrole,pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine,pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene,furan, thiazole, isothiazole, oxazole, isoxazole, indole, isoindole,quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine,cinnoline, benzothiophene, and benzofuran. Other heteroaryl groupsinclude those having from 5 to 8 ring members and from 1 to 3heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole,pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, andisoxazole. Some other heteroaryl groups include those having from 9 to12 ring members and from 1 to 3 heteroatoms, such as indole, isoindole,quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine,cinnoline, benzothiophene, benzofuran and bipyridine. Still otherheteroaryl groups include those having from 5 to 6 ring members and from1 to 2 ring heteroatoms including N, O or S, such as pyrrole, pyridine,imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan,thiazole, isothiazole, oxazole, and isoxazole.

Some heteroaryl groups include from 5 to 10 ring members and onlynitrogen heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole,triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and1,3,5-isomers), indole, isoindole, quinoline, isoquinoline, quinoxaline,quinazoline, phthalazine, and cinnoline. Other heteroaryl groups includefrom 5 to 10 ring members and only oxygen heteroatoms, such as furan andbenzofuran. Some other heteroaryl groups include from 5 to 10 ringmembers and only sulfur heteroatoms, such as thiophene andbenzothiophene. Still other heteroaryl groups include from 5 to 10 ringmembers and at least two heteroatoms, such as imidazole, pyrazole,triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and1,3,5-isomers), thiazole, isothiazole, oxazole, isoxazole, quinoxaline,quinazoline, phthalazine, and cinnoline.

“Heteroatoms” refers to O, S, or N.

“Salt” refers to acid or base salts of the compounds used in the methodsdisclosed herein. Illustrative examples of pharmaceutically-acceptablesalts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoricacid, and the like) salts, organic acid (acetic acid, propionic acid,glutamic acid, citric acid, and the like) salts, and quaternary ammonium(methyl iodide, ethyl iodide, and the like) salts. It is understood thatthe pharmaceutically-acceptable salts are non-toxic. Additionalinformation on suitable pharmaceutically-acceptable salts can be foundin Remington's Pharmaceutical Sciences, 17th ed., Mack PublishingCompany, Easton, Pa., 1985, which is incorporated herein by reference.

“Isomers” refers to compounds with the same chemical formula but whichare structurally distinguishable.

“Tautomer” refers to one of two or more structural isomers which existin equilibrium and which are readily converted from one form to another.

Descriptions of compounds discussed herein are limited by principles ofchemical bonding known to those skilled in the art. Accordingly, where agroup may be substituted by one or more of a number of substituents,such substitutions are selected so as to comply with principles ofchemical bonding and to produce compounds which are not inherentlyunstable—and/or would be known to one of ordinary skill in the art aslikely to be unstable under ambient conditions—such as aqueous, neutral,or physiological conditions.

“Pharmaceutically-acceptable excipient” and “pharmaceutically-acceptablecarrier” refer to a substance that aids the administration of an activeagent to—and absorption by—a subject and can be included in thecompositions discussed herein without causing a significant adversetoxicological effect on the patient. Non-limiting examples ofpharmaceutically-acceptable excipients include water, NaCl, normalsaline solutions, lactated Ringer's, normal sucrose, normal glucose,binders, fillers, disintegrants, lubricants, coatings, sweeteners,flavors and colors, and the like. One of ordinary skill in the art willrecognize that other pharmaceutical excipients are useful incompositions for use in the methods disclosed herein.

C. GR Positive (GR⁺) Neuroepithelial Tumors

The methods disclosed herein are useful for treating a GR⁺neuroepithelial tumor by administering an effective amount of SGRM.Neuroepithelial tumors arise from cells that developmentally stem fromprimitive neuroepithelia and represent the largest group of intracranialneoplasms. See, e.g., the “Oncology Encyclopedia” article at the link“CNS-tumors/Diagnoses/Intracranial-tumors/Background/Histology” on theoncolex.org website entitled “Histology of Intracranial Tumors”. Basedon the premise that each type of tumor results from the abnormal growthof a specific cell type, neuroepithelial tumors can be categorized intothe following classes according to the World Health Organization (WHO):astrocytic tumors, oligodendroglial tumors, ependymal cell tumors, mixedgliomas, neuroepithelial tumors of uncertain origin, tumors of thechoroid plexus, neuronal and mixed neuronal-glial tumors, pinealparenchyma tumors, and tumors with neuroblastic or glioblastic elements(embryonal tumors).

GR expression status in these various neuroepithelial tumors areexamined by using one or more of the routine biochemical analyses. Insome embodiments, GR expression is determined by detecting GR transcriptexpression, using methods such as microarray and RT-PCR. In otherembodiments, GR expression is determined by detecting proteinexpression, using methods such as, western blot analysis andimmunohistochemistry staining. In yet other embodiments, the GRexpression is determined using a combination of these methods.

In a preferred embodiment, immunohistochemistry staining is performedand a H-score method is used to quantify the expression of GR on tumortissues. In one exemplar assay, Formalin-fixed, paraffin-embedded tumortissue sections are deparaffinized and treated with antigen retrievalsolution to render the glucocorticoid receptors readily accessible toanti-GR antibodies. Anti-GR antibodies are then incubated with thetissue sections and the antibodies bound to the GR on the tissuesections are detected by addition of a horse peroxidase (HRP) conjugatedsecondary antibody that recognizes the anti-GR antibody. The HRP on thesecondary antibody conjugate catalyzes a colorimetric reaction and uponcontacting the appropriate substrate, produces a staining in thelocations where GR is present. In one approach, the intensity level ofthe GR staining is represented by 0 for negative staining, 1+ for weakstaining, 2+ for moderate staining, and 3+ for strong staining, (see thearticle entitled “ihc scoring” available at www.ihcworld.com). Thepercentage of GR⁺ cells of each intensity level is multiplied with theintensity level, and the results for all intensity levels are summed togenerate a H-score between 0-300. In one embodiment, the tumor typehaving a H-score equal to or higher than a predetermined threshold isconsidered GR⁺ tumor. In a preferred embodiment, the threshold is 150.In another embodiment, a GR⁺ tumor is one that has at least 10% tumorcells showing GR staining at any intensity.

D. Diagnosing Meningioma, Schwannoma, and Ependymoma

Schwannoma, meningioma, and ependymoma are neuroepithelial tumors andare typically GR⁺. These tumors are frequently observed in patients withNeurofibromatosis type 2 (“NF2”, a.k.a. “MISME Syndrome”, for “MultipleInherited Schwannomas, Meningiomas, and Ependymomas”). NF2 is caused bymutations in the NF2 gene, which gives a person an increased risk ofdeveloping cancerous and benign tumors and other symptoms of NF2. TheNF2 gene encodes a protein called merlin (also known as schwannomin).This protein is produced in the nervous system, particularly in Schwanncells, which surround and insulate nerve cells (neurons) in the brainand spinal cord. The merlin protein acts as a tumor suppressor andmutations in the NF2 gene lead to the production of a nonfunctionalversion of the merlin protein that cannot regulate the growth anddivision of cells.

Signs of NF2 usually develop in late teenage years or early 20s. NF2patients have an increased risk of developing cataracts in the eyes andbenign skin tumors and may have light brown pigmentation in their skin.Symptoms of NF2 often include hearing loss, tinnitus, dysequilibrium,headache, facial numbness and weakness. NF2 Patients may also exhibitabnormal corneal reflex, nystagmus, facial hypesthesia upon clinicalexaminations and show enlargement of the porus acousticus internus inthe CT scan, enhancing tumours in the region of cerebello-pontine anglein gadolinium-enhanced MRI scans, hearing loss in audiometric studiesand perhaps pathological findings in Electronystagmography. Genetictesting for mutations in the NF2 gene is available for patientsdiagnosed with NF2 to confirm the diagnosis.

Patients having meningioma may exhibit symptoms comprising one or moreof the following: changes in vision, such as double vision orblurriness; hearing loss; memory loss; loss of smell; facial pain;headaches that worsen with time; personality changes; weakness in an armor leg; and seizures. One or more of imaging based methods, such as,magnetic resonance imaging (MRI), computed tomography (CT), X-ray,cerebral angiogram, and positron emission tomography (PET) scan, orultrasonography (US), are often performed on subjects suspected ofhaving meningioma, e.g., based on exhibition of the related clinicalsymptoms. Results from these imaging tests are often combined with thepatient's medical history, physical examination and neurological teststo provide accurate diagnosis as well as information regarding theorigin of the meningioma and whether or where it has spread.

Common symptoms of schwannoma include, but are not limited to, one ormore of the following: one-sided hearing loss and buzzing or ringing inthe ear, dizziness, facial paralysis, difficulty in swallowing, impairedeye movement, taste disturbances, and unsteadiness, altered facial andcorneal sensation, nystagmus, ataxia. Imaging based methods, e.g., thoseas disclosed above, can also be performed to confirm the presence ofschwannoma.

Common symptoms of ependymoma include, but are not limited to, one ormore of the following: severe headache, visual loss, vomiting, bilateralBabinski sign, drowsiness (after several hours of the above symptoms),gait change (rotation of feet when walking), and constipation. Imagingbased methods, e.g., those as described above, can also be used toconfirm the presence of ependymoma.

In some cases, a biopsy, often obtained at the time when the tumor isbeing surgically removed, is analyzed to further confirm the presence ofNF 2, e.g., meningioma, schwannoma, or ependymoma.

E. Glucocorticoid Receptor Modulators (GRM)

Generally, treatment of an GR⁺ neuroepithelial tumor, e.g., schwannoma,meningioma, or ependymoma, can be provided by administering an effectiveamount of a SGRM of any chemical structure or mechanism of action.Provided herein, are classes of exemplary GRMs and specific members ofsuch classes. However, one of skill in the art will readily recognizeother related or unrelated SGRMs that can be employed in the treatmentmethods described herein.

1. GRMs Having a Steroidal Backbone

In some embodiments, an effective amount of a SGRM with a steroidalbackbone is administered to a subject for cancer treatment. SteroidalGRMs can be obtained by modification of the basic structure ofglucocorticoid agonists, i.e., varied forms of the steroid backbone. Thestructure of cortisol can be modified in a variety of ways. The two mostcommonly known classes of structural modifications of the cortisolsteroid backbone to create GRMs include modifications of the 11-βhydroxy group and modification of the 17-β side chain (See, e.g.,Lefebvre, J. Steroid Biochem. 33:557-563, 1989).

Examples of steroidal GRMs, including steroidal SGRMs, includeandrogen-type steroidal compounds as described in U.S. Pat. No.5,929,058, and the compounds disclosed in U.S. Pat. Nos. 4,296,206;4,386,085; 4,447,424; 4,477,445; 4,519,946; 4,540,686; 4,547,493;4,634,695; 4,634,696; 4,753,932; 4,774,236; 4,808,710; 4,814,327;4,829,060; 4,861,763; 4,912,097; 4,921,638; 4,943,566; 4,954,490;4,978,657; 5,006,518; 5,043,332; 5,064,822; 5,073,548; 5,089,488;5,089,635; 5,093,507; 5,095,010; 5,095,129; 5,132,299; 5,166,146;5,166,199; 5,173,405; 5,276,023; 5,380,839; 5,348,729; 5,426,102;5,439,913; 5,616,458, 5,696,127, and 6,303,591. Such steroidal GRantagonists include cortexolone, dexamethasone-oxetanone,19-nordeoxycorticosterone, 19-norprogesterone, cortisol-21-mesylate;dexamethasone-21-mesylate,11β-(4-dimethylaminoethoxyphenyl)-17α-propynyl-17β-hydroxy-4,9-estradien-3-one(RU009), and(17α)-17-hydroxy-19-(4-methylphenyl)androsta-4,9(11)-dien-3-one (RU044).

Other examples of steroidal antiglucocorticoids are disclosed in VanKampen et al. (2002) Eur. J. Pharmacol. 457(2-3):207, WO 03/043640, EP 0683 172 B1, and EP 0 763 541 B1, each of which is incorporated herein byreference. EP 0 763 541 B1 and Hoyberg et al., Int'l J. ofNeuro-psychopharmacology, 5:Supp. 1, S148 (2002) disclose the compound(11β,17β)-11-(1,3-benzodioxol-5-yl)-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one(ORG 34517), which in one embodiment, is administered in an amounteffective to treat an ACTH-secreting tumor in a subject.

2. Removal or Substitution of the 11-β Hydroxy Group

GRMs, including SGRMs, with modified steroidal backbones comprisingremoval or substitution of the 11-β hydroxy group are administered inone embodiment of the methods disclosed herein. This class includesnatural GRMs, including cortexolone, progesterone and testosteronederivatives, and synthetic compositions, such as mifepristone (Lefebvre,et al. supra). Preferred embodiments of the methods disclosed hereininclude all 11-β aryl steroid backbone derivatives because, in somecases, these compounds can be devoid of progesterone receptor (PR)binding activity (Agarwal, FEBS 217:221-226, 1987). In anotherembodiment an 11-β phenyl-aminodimethyl steroid backbone derivative,which is both an effective anti-glucocorticoid and anti-progesteroneagent, is administered. These compositions can act as reversibly-bindingsteroid receptor antagonists. For example, when bound to a 11-βphenyl-aminodimethyl steroid, the steroid receptor can be maintained ina conformation that cannot bind its natural ligand, such as cortisol inthe case of GR (Cadepond, 1997, supra).

Synthetic 11-beta phenyl-aminodimethyl steroids include mifepristone,also known as RU486, or 17-β-hydrox-11-β-(4-dimethyl-aminophenyl)17-α-(1-propynyl)estra-4,9-dien-3-one). Mifepristone has been shown tobe a powerful antagonist of both the progesterone and glucocorticoid(GR) receptors. Thus, in some embodiments, the GRM administered to treata GR⁺ neuroepithelial tumor or an ACTH-secreting tumor is mifepristone,or a salt, tautomer, or derivative thereof. In other embodiments,however, administration of mifepristone is specifically excluded as aGRM for treatment of a GR⁺ neuroepithelial tumor. In other embodiments,however, administration of mifepristone is specifically excluded as aGRM for treatment of an ACTH-secreting tumor.

Another 11-β phenyl-aminodimethyl steroid shown to have GR antagonisteffects includes the dimethyl aminoethoxyphenyl derivative RU009(RU39,009),11-β-(4-dimethyl-aminoethoxyphenyl)-17-α-(propynyl-17-β-hydroxy-4,9-estradien-3-one)(see Bocquel, J. Steroid Biochem. Mol. Biol. 45:205-215, 1993). AnotherGR antagonist related to RU486 is RU044 (RU43,044)17-β-hydrox-17-α-19-(4-methyl-phenyl)-androsta-4,9(11)-dien-3-one)(Bocquel, 1993, supra). See also Teutsch, Steroids 38:651-665, 1981;U.S. Pat. Nos. 4,386,085 and 4,912,097.

One embodiment includes compositions that are irreversibleanti-glucocorticoids. Such compounds include α-keto-methanesulfonatederivatives of cortisol, including cortisol-21-mesylate(4-pregnene-11-β, 17-α, 21-triol-3, 20-dione-21-methane-sulfonate anddexamethasone-21-mesylate (16-methyl-9-α-fluoro-1,4-pregnadiene-11β,17-α, 21-triol-3, 20-dione-21-methane-sulfonate). See Simons, J. SteroidBiochem. 24:25-32, 1986; Mercier, J. Steroid Biochem. 25:11-20, 1986;U.S. Pat. No. 4,296,206.

3. Modification of the 17-Beta Side Chain Group

Steroidal anti-glucocorticoids which can be obtained by variousstructural modifications of the 17-β side chain are also used in themethods disclosed herein. This class includes syntheticantiglucocorticoids, such as dexamethasone-oxetanone, various 17,21-acetonide derivatives and 17-beta-carboxamide derivatives ofdexamethasone (Lefebvre, 1989, supra; Rousseau, Nature 279:158-160,1979).

4. Other Steroid Backbone Modifications

GRMs, including SGRMs, used in the various embodiments of the methodsdisclosed herein include any steroid backbone modification which effectsa biological response resulting from a GR-agonist interaction. Steroidbackbone antagonists can be any natural or synthetic variation ofcortisol, such as adrenal steroids missing the C-19 methyl group, suchas 19-nordeoxycorticosterone and 19-norprogesterone (Wynne,Endocrinology 107:1278-1280, 1980).

In general, the 11-β side chain substituent, and particularly the sizeof that substituent, can play a key role in determining the extent of asteroid's antiglucocorticoid activity. Substitutions in the A ring ofthe steroid backbone can also be important. For example,17-hydroxypropenyl side chains can, in some cases, decreaseantiglucocorticoid activity in comparison to 17-propynyl side chaincontaining compounds.

Additional glucocorticoid receptor antagonists known in the art andsuitable for practice of the methods disclosed herein include21-hydroxy-6,19-oxidoprogesterone (See Vicent, Mol. Pharm. 52:749-753,1997), Org31710 (See Mizutani, J Steroid Biochem Mol Biol 42(7):695-704,1992), RU43044, RU40555 (See Kim, J Steroid Biochem Mol Biol.67(3):213-22, 1998), and RU28362.

5. Nonsteroidal Anti-Glucocorticoid Receptors Modulators

Provided herein, are classes of exemplary nonsteroidal glucocorticoidreceptor modulator (GRM) and specific members of such classes that canbe used for the methods disclosed herein. Such nonsteroidal GRMs may benonsteroidal SGRMs. However, one of skill in the art will readilyrecognize other related or unrelated glucocorticoid receptor modulatorsthat can be employed in the treatment methods described herein. Theseinclude synthetic mimetics and analogs of proteins, including partiallypeptidic, pseudopeptidic and non-peptidic molecular entities. Forexample, oligomeric peptidomimetics useful in the methods disclosedherein include (α-β-unsaturated) peptidosulfonamides, N-substitutedglycine derivatives, oligo carbamates, oligo urea peptidomimetics,hydrazinopeptides, oligosulfones and the like (See, e.g., Amour, Int. J.Pept. Protein Res. 43:297-304, 1994; de Bont, Bioorganic &MedicinalChem. 4:667-672, 1996).

Examples of nonsteroidal GR modulators include the GR antagonistcompounds disclosed in U.S. Pat. Nos. 5,696,127; 6,570,020; and6,051,573; the GR antagonist compounds disclosed in US PatentApplication 20020077356, the glucocorticoid receptor antagonistsdisclosed in Bradley et al., J. Med. Chem. 45, 2417-2424 (2002), e.g.,4α(S)-benzyl-2(R)-chloroethynyl-1,2,3,4,4a,9,10,10α(R)-octahydro-phenanthrene-2,7-diol(“CP 394531”) and4α(S)-benzyl-2(R)-prop-1-ynyl-1,2,3,4,4α,9,10,10α(R)-octahydro-phenanthrene-2,7-diol(“CP 409069”); and the compounds disclosed in PCT InternationalApplication No. WO 96/19458, which describes non-steroidal compoundswhich are high-affinity, highly selective antagonists for steroidreceptors, such as 6-substituted-1,2-dihydro-N-protected-quinolines.

For additional compounds that can be utilized in the methods disclosedherein and in methods of identifying and making compounds useful inpracticing these methods, see U.S. Pat. No. 4,296,206 (see above); U.S.Pat. No. 4,386,085 (see above); U.S. Pat. Nos. 4,447,424; 4,477,445;4,519,946; 4,540,686; 4,547,493; 4,634,695; 4,634,696; 4,753,932;4,774,236; 4,808,710; 4,814,327; 4,829,060; 4,861,763; 4,912,097;4,921,638; 4,943,566; 4,954,490; 4,978,657; 5,006,518; 5,043,332;5,064,822; 5,073,548; 5,089,488; 5,089,635; 5,093,507; 5,095,010;5,095,129; 5,132,299; 5,166,146; 5,166,199; 5,173,405; 5,276,023;5,380,839; 5,348,729; 5,426,102; 5,439,913; and 5,616,458; and WO96/19458, which describes non-steroidal compounds which arehigh-affinity, highly selective modulators (antagonists) for steroidreceptors, such as 6-substituted-1,2-dihydro N-1 protected quinolines.

In some embodiments, the combination therapy for treating cancerinvolves a nonsteroidal GRM having a fused azadecalin backbone, aheteroaryl ketone fused azadecalin backbone, or an octahydro fusedazadecalin backbone.

Exemplary GRMs having a fused azadecalin backbone include thosedescribed in U.S. Pat. Nos. 7,928,237; 8,461,172; and 8,557,839, allthree of which patents are hereby incorporated by reference in theirentireties. In some cases, the GRM having a fused azadecalin backbonehas the following structure:

-   -   wherein    -   L¹ and L² are members independently selected from a bond and        unsubstituted alkylene;    -   R¹ is a member selected from unsubstituted alkyl, unsubstituted        heteroalkyl, unsubstituted heterocycloalkyl, —OR^(1A),        —NR^(1C)R^(1D), —C(O)NR^(1C)R^(1D), and —C(O)OR^(1A), wherein    -   R^(1A) is a member selected from hydrogen, unsubstituted alkyl        and unsubstituted heteroalkyl,    -   R^(1C) and R^(1D) are members independently selected from        unsubstituted alkyl and unsubstituted heteroalkyl,    -   wherein R^(1C) and R^(1D) are optionally joined to form an        unsubstituted ring with the nitrogen to which they are attached,        wherein said ring optionally comprises an additional ring        nitrogen;    -   R² has the formula:

-   -   wherein    -   R^(2G) is a member selected from hydrogen, halogen,        unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted        cycloalkyl, unsubstituted heterocycloalkyl, —CN, and —CF₃;    -   J is phenyl;    -   t is an integer from 0 to 5;    -   X is —S(O₂)—; and    -   R⁵ is phenyl optionally substituted with 1-5 R^(5A) groups,        wherein    -   R^(5A) is a member selected from hydrogen, halogen, —OR^(5A1),        —S(O₂)NR^(5A2)R^(5A3), —CN, and unsubstituted alkyl, wherein    -   R^(5A1) is a member selected from hydrogen and unsubstituted        alkyl, and    -   R^(5A2) and R^(5A3) are members independently selected from        hydrogen and unsubstituted alkyl,    -   or salts and isomers thereof.

Compounds containing fused azadecalin backbones can be prepared asdescribed in U.S. Pat. No. 7,928,237. For example, fused azadecalinbackbones can be prepared as described in Scheme 1, where, R⁵, R^(1A),R^(1C), R^(1D), L² and R² are as defined above in the compounds usefulin the practice of the methods disclosed herein. In Scheme 1, L²-R² canbe replaced by a suitable protecting group, such as BOC or benzyl, tofacilitate the synthesis. Keto-ester 1 is converted directly to enone 3by a Robinson annelation reaction involving treatment of 1 with a base(e.g. potassium or sodium alkoxides) in an alcohol solvent (e.g.methanol, ethanol, or tert-butanol) followed by addition of methylvinylketone (MVK). The reaction is typically carried out at 0-250° C.

Exemplary GRMs having a heteroaryl ketone fused azadecalin backboneinclude those described in U.S. 2014/0038926, now U.S. Pat. No.8,859,774, hereby incorporated by reference herein in its entirety. Insome cases, the GRM having a heteroaryl ketone fused azadecalin backbonehas the following structure:

wherein

-   -   R¹ is a heteroaryl ring having from 5 to 6 ring members and from        1 to 4 heteroatoms each independently selected from the group        consisting of N, O and S, optionally substituted with 1-4 groups        each independently selected from R^(1a);    -   each R^(1a) is independently selected from the group consisting        of hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,        C₁₋₆ haloalkoxy, —CN, N-oxide, C₃₋₈ cycloalkyl, and C₃₋₈        heterocycloalkyl;    -   ring J is selected from the group consisting of a cycloalkyl        ring, a heterocycloalkyl ring, an aryl ring and a heteroaryl        ring, wherein the heterocycloalkyl and heteroaryl rings have        from 5 to 6 ring members and from 1 to 4 heteroatoms each        independently selected from the group consisting of N, O and S;    -   each R² is independently selected from the group consisting of        hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆        haloalkoxy, C₁₋₆ alkyl-C₁₋₆ alkoxy, —CN, —OH, —NR^(2a)R^(2b),        —C(O)R^(2a), —C(O)OR^(2a), —C(O)NR^(2a)R^(2b), —SR^(2a),        —S(O)R^(2a), —S(O)₂ R^(2a), C₃₋₈ cycloalkyl, and C₃₋₈        heterocycloalkyl, wherein the heterocycloalkyl groups are        optionally substituted with 1-4 R^(2c) groups;    -   alternatively, two R² groups linked to the same carbon are        combined to form an oxo group (═O);    -   alternatively, two R² groups are combined to form a        heterocycloalkyl ring having from 5 to 6 ring members and from 1        to 3 heteroatoms each independently selected from the group        consisting of N, O and S, wherein the heterocycloalkyl ring is        optionally substituted with from 1 to 3 R^(2d) groups;    -   R^(2a) and R^(2b) are each independently selected from the group        consisting of hydrogen and C₁₋₆ alkyl;    -   each R^(2c) is independently selected from the group consisting        of hydrogen, halogen, hydroxy, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,        —CN, and —NR^(2a)R^(2b);    -   each R^(2d) is independently selected from the group consisting        of hydrogen and C₁₋₆ alkyl, or two R^(2d) groups attached to the        same ring atom are combined to form (═O);    -   R³ is selected from the group consisting of phenyl and pyridyl,        each optionally substituted with 1-4 R^(3a) groups;    -   each R^(3a) is independently selected from the group consisting        of hydrogen, halogen, and C₁₋₆ haloalkyl; and    -   subscript n is an integer from 0 to 3;    -   or salts and isomers thereof.

Compounds containing fused azadecalin backbones can be prepared asdescribed in Scheme 2.

Exemplary GRMs having an octahydro fused azadecalin backbone includethose described in U.S. patent application Ser. No. 14/549,885, entitledOctahydro Fused Azadecalin Glucocorticoid Receptor Modulators, publishedas U.S. Patent Publication 2015-0148341, the entire contents of which ishereby incorporated by reference herein in its entirety. In some cases,the GRM having an octahydro fused azadecalin backbone has the followingstructure:

wherein

-   -   R¹ is a heteroaryl ring having from 5 to 6 ring members and from        1 to 4 heteroatoms each independently selected from the group        consisting of N, O and S, optionally substituted with 1-4 groups        each independently selected from R^(1a);    -   each R^(1a) is independently selected from the group consisting        of hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,        C₁₋₆ haloalkoxy, N-oxide, and C₃₋₈ cycloalkyl;    -   ring J is selected from the group consisting of an aryl ring and        a heteroaryl ring having from 5 to 6 ring members and from 1 to        4 heteroatoms each independently selected from the group        consisting of N, O and S;    -   each R² is independently selected from the group consisting of        hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆        haloalkoxy, C₁₋₆ alkyl-C₁₋₆ alkoxy, —CN, —OH, —NR^(2a)R^(2b),        —C(O)R^(2a), —C(O)OR^(2a), —C(O)NR^(2a)R^(2b), —SR^(2a),        —S(O)R^(2a), —S(O)₂ R^(2a), C₃₋₈ cycloalkyl, and C₃₋₈        heterocycloalkyl having from 1 to 3 heteroatoms each        independently selected from the group consisting of N, O and S;    -   alternatively, two R² groups on adjacent ring atoms are combined        to form a heterocycloalkyl ring having from 5 to 6 ring members        and from 1 to 3 heteroatoms each independently selected from the        group consisting of N, O and S, wherein the heterocycloalkyl        ring is optionally substituted with from 1 to 3 R^(2c) groups;    -   R^(2a), R^(2b) and R^(2c) are each independently selected from        the group consisting of hydrogen and C₁₋₆ alkyl;    -   each R^(3a) is independently halogen; and    -   subscript n is an integer from 0 to 3;        or salts and isomers thereof.

Compounds containing octahydro fused azadecalin backbones can beprepared as described in Scheme 3.

F. Identifying Selective Glucocorticoid Receptor Modulators (SGRMS)

To determine whether a test compound is a SGRM, the compound is firstsubjected to assays to measure its ability to bind to the GR and inhibitGR-mediated activities, which determines whether the compound is aglucocorticoid receptor modulator. The compound, if confirmed to be aglucocorticoid receptor modulator, is then subjected to a selectivitytest to determine whether the compound can bind specifically to GR ascompared to non-GR proteins, such as the estrogen receptor, theprogesterone receptor, the androgen receptor, or the mineralocorticoidreceptor. In one embodiment, a SGRM binds to GR at a substantiallyhigher affinity, e.g., at least 10 times higher affinity, than to non-GRproteins. A SGRM may exhibit a 100 fold, 1000 fold or greaterselectivity for binding to GR relative to binding to non-GR proteins.

i. Binding

A test compounds' ability to bind to the glucocorticoid receptor can bemeasured using a variety of assays, for example, by screening for theability of the test compound to compete with a glucocorticoid receptorligand, such as dexamethasone, for binding to the glucocorticoidreceptor. Those of skill in the art will recognize that there are anumber of ways to perform such competitive binding assays. In someembodiments, the glucocorticoid receptor is pre-incubated with a labeledglucocorticoid receptor ligand and then contacted with a test compound.This type of competitive binding assay may also be referred to herein asa binding displacement assay. A decrease of the quantity of labeledligand bound to glucocorticoid receptor indicates that the test compoundbinds to the glucocorticoid receptor. In some cases, the labeled ligandis a fluorescently labeled compound (e.g., a fluorescently labeledsteroid or steroid analog). Alternatively, the binding of a testcompound to the glucocorticoid receptor can be measured directly with alabeled test compound. This latter type of assay is called a directbinding assay.

Both direct binding assays and competitive binding assays can be used ina variety of different formats. The formats may be similar to those usedin immunoassays and receptor binding assays. For a description ofdifferent formats for binding assays, including competitive bindingassays and direct binding assays, see Basic and Clinical Immunology 7thEdition (D. Stites and A. Terr ed.) 1991; Enzyme Immunoassay, E. T.Maggio, ed., CRC Press, Boca Raton, Fla. (1980); and “Practice andTheory of Enzyme Immunoassays,” P. Tijssen, Laboratory Techniques inBiochemistry and Molecular Biology, Elsevier Science Publishers B.V.Amsterdam (1985), each of which is incorporated herein by reference.

In solid phase competitive binding assays, for example, the samplecompound can compete with a labeled analyte for specific binding siteson a binding agent bound to a solid surface. In this type of format, thelabeled analyte can be a glucocorticoid receptor ligand and the bindingagent can be glucocorticoid receptor bound to a solid phase.Alternatively, the labeled analyte can be labeled glucocorticoidreceptor and the binding agent can be a solid phase glucocorticoidreceptor ligand. The concentration of labeled analyte bound to thecapture agent is inversely proportional to the ability of a testcompound to compete in the binding assay.

Alternatively, the competitive binding assay may be conducted in theliquid phase, and any of a variety of techniques known in the art may beused to separate the bound labeled protein from the unbound labeledprotein. For example, several procedures have been developed fordistinguishing between bound ligand and excess bound ligand or betweenbound test compound and the excess unbound test compound. These includeidentification of the bound complex by sedimentation in sucrosegradients, gel electrophoresis, or gel isoelectric focusing;precipitation of the receptor-ligand complex with protamine sulfate oradsorption on hydroxylapatite; and the removal of unbound compounds orligands by adsorption on dextran-coated charcoal (DCC) or binding toimmobilized antibody. Following separation, the amount of bound ligandor test compound is determined.

Alternatively, a homogenous binding assay may be performed in which aseparation step is not needed. For example, a label on theglucocorticoid receptor may be altered by the binding of theglucocorticoid receptor to its ligand or test compound. This alterationin the labeled glucocorticoid receptor results in a decrease or increasein the signal emitted by label, so that measurement of the label at theend of the binding assay allows for detection or quantitation of theglucocorticoid receptor in the bound state. A wide variety of labels maybe used. The component may be labeled by any one of several methods.Useful radioactive labels include those incorporating ³H, ¹²⁵I, ³⁵S,¹⁴C, or ³²P. Useful non-radioactive labels include those incorporatingfluorophores, chemiluminescent agents, phosphorescent agents,electrochemiluminescent agents, and the like. Fluorescent agents areespecially useful in analytical techniques that are used to detectshifts in protein structure such as fluorescence anisotropy and/orfluorescence polarization. The choice of label depends on sensitivityrequired, case of conjugation with the compound, stability requirements,and available instrumentation. For a review of various labeling orsignal producing systems which may be used, see U.S. Pat. No. 4,391,904,which is incorporated herein by reference in its entirety for allpurposes. The label may be coupled directly or indirectly to the desiredcomponent of the assay according to methods well known in the art. Insome cases, a test compound is contacted with a GR in the presence of afluorescently labeled ligand (e.g., a steroid or steroid analog) with aknown affinity for the GR, and the quantity of bound and free labeledligand is estimated by measuring the fluorescence polarization of thelabeled ligand.

ii. Activity

1) HepG2 Tyrosine Aminotransferase (TAT) Assay

Compounds that have demonstrated the desired binding affinity to GR aretested for their activity in inhibiting GR mediated activities. Thecompounds are typically subject to a Tyrosine Aminotransferase Assay(TAT), which assesses the ability of a test compound to inhibit theinduction of tyrosine aminotransferase activity by dexamethasone. SeeExample 1. GR modulators that are suitable for the method disclosedherein have an IC₅₀ (half maximal inhibition concentration) of less than10 micromolar. Other assays, including but not limited to thosedescribed below, can also be deployed to confirm the GR modulationactivity of the compounds.

2) Cell-Based Assays

Cell-based assays which involve whole cells or cell fractions containingglucocorticoid receptors can also be used to assay for a test compound'sbinding or modulation of activity of the glucocorticoid receptor.Exemplary cell types that can be used according to the methods disclosedherein include, e.g., any mammalian cells including leukocytes such asneutrophils, monocytes, macrophages, eosinophils, basophils, mast cells,and lymphocytes, such as T cells and B cells, leukemia cells, Burkitt'slymphoma cells, tumor cells (including mouse mammary tumor virus cells),endothelial cells, fibroblasts, cardiac cells, muscle cells, breasttumor cells, ovarian cancer carcinomas, cervical carcinomas,glioblastomas, liver cells, kidney cells, and neuronal cells, as well asfungal cells, including yeast. Cells can be primary cells or tumor cellsor other types of immortal cell lines. Of course, the glucocorticoidreceptor can be expressed in cells that do not express an endogenousversion of the glucocorticoid receptor.

In some cases, fragments of the glucocorticoid receptor, as well asprotein fusions, can be used for screening. When molecules that competefor binding with the glucocorticoid receptor ligands are desired, the GRfragments used are fragments capable of binding the ligands (e.g.,dexamethasone). Alternatively, any fragment of GR can be used as atarget to identify molecules that bind the glucocorticoid receptor.Glucocorticoid receptor fragments can include any fragment of, e.g., atleast 20, 30, 40, 50 amino acids up to a protein containing all but oneamino acid of glucocorticoid receptor.

In some embodiments, a reduction in signaling triggered byglucocorticoid receptor activation is used to identify glucocorticoidreceptor modulators. Signaling activity of the glucocorticoid receptorcan be determined in many ways. For example, downstream molecular eventscan be monitored to determine signaling activity. Downstream eventsinclude those activities or manifestations that occur as a result ofstimulation of a glucocorticoid receptor. Exemplary downstream eventsuseful in the functional evaluation of transcriptional activation andantagonism in unaltered cells include upregulation of a number ofglucocorticoid response element (GRE)-dependent genes (PEPCK, tyrosineamino transferase, aromatase). In addition, specific cell typessusceptible to GR activation may be used, such as osteocalcin expressionin osteoblasts which is downregulated by glucocorticoids; primaryhepatocytes which exhibit glucocorticoid mediated upregulation of PEPCKand glucose-6-phosphate (G-6-Pase)). GRE-mediated gene expression hasalso been demonstrated in transfected cell lines using well-knownGRE-regulated sequences (e.g., the mouse mammary tumor virus promoter(MMTV) transfected upstream of a reporter gene construct). Examples ofuseful reporter gene constructs include luciferase (luc), alkalinephosphatase (ALP) and chloramphenicol acetyl transferase (CAT). Thefunctional evaluation of transcriptional repression can be carried outin cell lines such as monocytes or human skin fibroblasts. Usefulfunctional assays include those that measure IL-1beta stimulated IL-6expression; the downregulation of collagenase, cyclooxygenase-2 andvarious chemokines (MCP-1, RANTES); LPS stimulated cytokine release,e.g., TNFα; or expression of genes regulated by NFkB or AP-1transcription factors in transfected cell-lines.

Compounds that are tested in whole-cell assays can also be tested in acytotoxicity assay. Cytotoxicity assays are used to determine the extentto which a perceived effect is due to non-glucocorticoid receptorbinding cellular effects. In an exemplary embodiment, the cytotoxicityassay includes contacting a constitutively active cell with the testcompound. Any decrease in cellular activity indicates a cytotoxiceffect.

3) Additional Assays

Further illustrative of the many assays which can be used to identifycompositions utilized in the methods disclosed herein, are assays basedon glucocorticoid activities in vivo. For example, assays that assessthe ability of a putative GR modulator to inhibit uptake of 3H-thymidineinto DNA in cells which are stimulated by glucocorticoids can be used.Alternatively, the putative GR modulator can complete with3H-dexamethasone for binding to a hepatoma tissue culture GR (see, e.g.,Choi, et al., Steroids 57:313-318, 1992). As another example, theability of a putative GR modulator to block nuclear binding of3H-dexamethasone-GR complex can be used (Alexandrova et al., J. SteroidBiochem. Mol. Biol. 41:723-725, 1992). To further identify putative GRmodulators, kinetic assays able to discriminate between glucocorticoidagonists and modulators by means of receptor-binding kinetics can alsobe used (as described in Jones, Biochem J. 204:721-729, 1982).

In another illustrative example, the assay described by Daune, Molec.Pharm. 13:948-955, 1977; and in U.S. Pat. No. 4,386,085, can be used toidentify anti-glucocorticoid activity. Briefly, the thymocytes ofadrenalectomized rats are incubated in nutritive medium containingdexamethasone with the test compound (the putative GR modulator) atvarying concentrations. ³H-uridine is added to the cell culture, whichis further incubated, and the extent of incorporation of radiolabel intopolynucleotide is measured. Glucocorticoid agonists decrease the amountof ³H-uridine incorporated. Thus, a GR modulator will oppose thiseffect.

iii. Selectivity

The GR modulators selected above are then subject to a selectivity assayto determine whether they are SGRMs. Typically, selectivity assaysinclude testing a compound that binds glucocorticoid receptor in vitrofor the degree of binding to non-glucocorticoid receptor proteins.Selectivity assays may be performed in vitro or in cell based systems,as described above. Binding may be tested against any appropriatenon-glucocorticoid receptor protein, including antibodies, receptors,enzymes, and the like. In an exemplary embodiment, thenon-glucocorticoid receptor binding protein is a cell-surface receptoror nuclear receptor. In another exemplary embodiment, thenon-glucocorticoid receptor protein is a steroid receptor, such asestrogen receptor, progesterone receptor, androgen receptor, ormineralocorticoid receptor.

The selectivity of the antagonist for the GR relative to the MR can bemeasured using a variety of assays known to those of skill in the art.For example, specific antagonists can be identified by measuring theability of the antagonist to bind to the GR compared to the MR (see,e.g., U.S. Pat. Nos. 5,606,021; 5,696,127; 5,215,916; and 5,071,773).Such an analysis can be performed using either a direct binding assay orby assessing competitive binding to the purified GR or MR in thepresence of a known ligand. In an exemplary assay, cells that stablyexpress the glucocorticoid receptor or mineralocorticoid receptor (see,e.g., U.S. Pat. No. 5,606,021) at high levels are used as a source ofpurified receptor. The affinity of the ligand for the receptor is thendirectly measured. Those GR modulators that exhibit at least a 10-fold,a 100-fold higher affinity, and often a 1000-fold higher affinity, forthe GR relative to the MR are then selected for use in the methodsdisclosed herein.

The selectivity assay may also include assaying the ability to inhibitGR-mediated activities, but not MR-mediated activities. One method ofidentifying such a GR-specific modulator is to assess the ability of anantagonist to prevent activation of reporter constructs usingtransfection assays (see, e.g., Bocquel et al, J. Steroid Biochem Molec.Biol. 45:205-215, 1993; U.S. Pat. Nos. 5,606,021, 5,929,058). In anexemplary transfection assay, an expression plasmid encoding thereceptor and a reporter plasmid containing a reporter gene linked toreceptor-specific regulatory elements are co-transfected into suitablereceptor-negative host cells. The transfected host cells are thencultured in the presence and absence of a hormone, such as cortisol oran analog thereof, able to activate the hormone responsivepromoter/enhancer element of the reporter plasmid. Next the transfectedand cultured host cells are monitored for induction (i.e., the presence)of the product of the reporter gene sequence. Finally, the expressionand/or steroid binding-capacity of the hormone receptor protein (codedfor by the receptor DNA sequence on the expression plasmid and producedin the transfected and cultured host cells), is measured by determiningthe activity of the reporter gene in the presence and absence of anantagonist. The antagonist activity of a compound may be determined incomparison to known antagonists of the GR and MR receptors (see, e.g.,U.S. Pat. No. 5,696,127). Efficacy is then reported as the percentmaximal response observed for each compound relative to a referenceantagonist compound. GR modulators that exhibits at least a 100-fold,often 1000-fold or greater, activity towards the GR relative to the MR,PR, or AR are then selected for use in the methods disclosed herein.

An exemplar SGRM that can be used in the methods disclosed herein isCORT125134, i.e.,(R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,which has the following structure:

Another exemplar SGRM that can be used in the methods disclosed hereinis CORT125281, i.e.,((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,which has the following structure:

G. Pharmaceutical Compositions and Administration

In some embodiments, a pharmaceutical composition including apharmaceutically acceptable excipient and a nonsteroidal GRM are usefulin the practice of the methods disclosed herein.

Nonsteroidal GRMs can be prepared and administered in a wide variety oforal, parenteral and topical dosage forms. Oral preparations includetablets, pills, powder, dragees, capsules, liquids, lozenges, gels,syrups, slurries, suspensions, etc., suitable for ingestion by thepatient. Nonsteroidal GRMs can also be administered by injection, thatis, intravenously, intramuscularly, intracutaneously, subcutaneously,intraduodenally, or intraperitoneally. Also, nonsteroidal GRMs can beadministered by inhalation, for example, intranasally. Additionally,nonsteroidal GRMs can be administered transdermally. Accordingly,pharmaceutical compositions including a pharmaceutically acceptablecarrier or excipient and a nonsteroidal GRM are useful in the practiceof the methods disclosed herein.

For preparing pharmaceutical compositions from nonsteroidal GRMs,pharmaceutically acceptable carriers can be either solid or liquid.Solid form preparations include powders, tablets, pills, capsules,cachets, suppositories, and dispersible granules. A solid carrier can beone or more substances, which may also act as diluents, flavoringagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material. Details on techniques for formulation andadministration are well described in the scientific and patentliterature, see, e.g., the latest edition of Remington's PharmaceuticalSciences, Maack Publishing Co, Easton Pa. (“Remington's”).

In powders, the carrier is a finely divided solid, which is in a mixturewith the finely divided active component, a nonsteroidal GRM. Intablets, the active component is mixed with the carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired.

The powders and tablets preferably contain from 5% or 10% to 70% of theactive compound. Suitable carriers are magnesium carbonate, magnesiumstearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose, a lowmelting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as a carrier providing a capsule in which theactive component with or without other carriers, is surrounded by acarrier, which is thus in association with it. Similarly, cachets andlozenges are included. Tablets, powders, capsules, pills, cachets, andlozenges can be used as solid dosage forms suitable for oraladministration.

Suitable solid excipients are carbohydrate or protein tillers include,but are not limited to sugars, including lactose, sucrose, mannitol, orsorbitol; starch from corn, wheat, rice, potato, or other plants;cellulose such as methyl cellulose, hydroxypropylmethyl-cellulose, orsodium carboxymethylcellulose; and gums including arabic and tragacanth;as well as proteins such as gelatin and collagen. If desired,disintegrating or solubilizing agents may be added, such as thecross-linked polyvinyl pyrrolidone, agar, alginic acid, or a saltthereof, such as sodium alginate.

Dragee cores are provided with suitable coatings such as concentratedsugar solutions, which may also contain gum arabic, talc,polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titaniumdioxide, lacquer solutions, and suitable organic solvents or solventmixtures. Dyestuffs or pigments may be added to the tablets or drageecoatings for product identification or to characterize the quantity ofactive compound (i.e., dosage). Pharmaceutical preparations useful forthe practice of the methods pharmaceutical compositions including apharmaceutically acceptable carrier or excipient and a nonsteroidal GRMcan also be used orally using, for example, push-fit capsules made ofgelatin, as well as soft, sealed capsules made of gelatin and a coatingsuch as glycerol or sorbitol. Push-fit capsules can contain GR modulatormixed with a filler or binders such as lactose or starches, lubricantssuch as talc or magnesium stearate, and, optionally, stabilizers. Insoft capsules, the GR modulator compounds may be dissolved or suspendedin suitable liquids, such as fatty oils, liquid paraffin, or liquidpolyethylene glycol with or without stabilizers.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water/propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizers, and thickening agents as desired. Aqueous suspensionssuitable for oral use can be made by dispersing the finely dividedactive component in water with viscous material, such as natural orsynthetic gums, resins, methylcellulose, sodium carboxymethylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gumtragacanth and gum acacia, and dispersing or wetting agents such as anaturally occurring phosphatide (e.g., lecithin), a condensation productof an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate),a condensation product of ethylene oxide with a long chain aliphaticalcohol (e.g., heptadecaethylene oxycetanol), a condensation product ofethylene oxide with a partial ester derived from a fatty acid and ahexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensationproduct of ethylene oxide with a partial ester derived from fatty acidand a hexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate).The aqueous suspension can also contain one or more preservatives suchas ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, oneor more flavoring agents and one or more sweetening agents, such assucrose, aspartame or saccharin. Formulations can be adjusted forosmolarity.

Also included are solid form preparations, which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

Oil suspensions can be formulated by suspending a nonsteroidal GRM in avegetable oil, such as arachis oil, olive oil, sesame oil or coconutoil, or in a mineral oil such as liquid paraffin; or a mixture of these.The oil suspensions can contain a thickening agent, such as beeswax,hard paraffin or cetyl alcohol. Sweetening agents can be added toprovide a palatable oral preparation, such as glycerol, sorbitol orsucrose. These formulations can be preserved by the addition of anantioxidant such as ascorbic acid. As an example of an injectable oilvehicle, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. Thepharmaceutical formulations useful in the practice of the methodsdisclosed herein can also be in the form of oil-in-water emulsions. Theoily phase can be a vegetable oil or a mineral oil, described above, ora mixture of these. Suitable emulsifying agents includenaturally-occurring gums, such as gum acacia and gum tragacanth,naturally occurring phosphatides, such as soybean lecithin, esters orpartial esters derived from fatty acids and hexitol anhydrides, such assorbitan mono-oleate, and condensation products of these partial esterswith ethylene oxide, such as polyoxyethylene sorbitan mono-oleate. Theemulsion can also contain sweetening agents and flavoring agents, as inthe formulation of syrups and elixirs. Such formulations can alsocontain a demulcent, a preservative, or a coloring agent.

Nonsteroidal GRMs can be delivered by transdermally, by a topical route,formulated as applicator sticks, solutions, suspensions, emulsions,gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

Nonsteroidal GRAs can also be delivered as microspheres for slow releasein the body. For example, microspheres can be administered viaintradermal injection of drug-containing microspheres, which slowlyrelease subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645,1995; as biodegradable and injectable gel formulations (see, e.g., GaoPharm. Res. 12:857-863, 1995); or, as microspheres for oraladministration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674,1997). Both transdermal and intradermal routes afford constant deliveryfor weeks or months.

The pharmaceutical formulations useful in the practice of the methodsdisclosed herein can be provided as a salt and can be formed with manyacids, including but not limited to hydrochloric, sulfuric, acetic,lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble inaqueous or other protonic solvents that are the corresponding free baseforms. In other cases, the preparation may be a lyophilized powder in 1mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitol at a pH1 range of4.5 to 5.5, that is combined with buffer prior to use

In another embodiment, the formulations useful in the practice of themethods disclosed herein can be delivered by the use of liposomes whichfuse with the cellular membrane or are endocytosed, i.e., by employingligands attached to the liposome, or attached directly to theoligonucleotide, that bind to surface membrane protein receptors of thecell resulting in endocytosis. By using liposomes, particularly wherethe liposome surface carries ligands specific for target cells, or areotherwise preferentially directed to a specific organ, one can focus thedelivery of the GR modulator into the target cells in vivo. (See, e.g.,Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin.Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46:1576-1587,1989).

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the active component, a nonsteroidal GRA. Theunit dosage form can be a packaged preparation, the package containingdiscrete quantities of preparation, such as packeted tablets, capsules,and powders in vials or ampoules. Also, the unit dosage form can be acapsule, tablet, cachet, or lozenge itself, or it can be the appropriatenumber of any of these in packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 0.1 mg to 10000 mg, more typically 1.0 mg to6000 mg, most typically 600 mg to 1200 mg. Suitable dosages also includeabout 1 mg, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400,500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700,1800, 1900, or 2000 mg, according to the particular application and thepotency of the active component. The composition can, if desired, alsocontain other compatible therapeutic agents.

Single or multiple administrations of formulations can be administereddepending on the dosage and frequency as required and tolerated by thepatient. The formulations should provide a sufficient quantity of activeagent to effectively treat the disease state. Thus, in one embodiment,the pharmaceutical formulation for oral administration of a nonsteroidalGRM is in a daily amount of between about 0.01 to about 150 mg perkilogram of body weight per day (mg/kg/day). In some embodiments, thedaily amount is from about 1.0 to 100 mg/kg/day, 5 to 50 mg/kg/day, 10to 30 mg/kg/day, and 10 to 20 mg/kg/day. Lower dosages can be used,particularly when the drug is administered to an anatomically secludedsite, such as the cerebral spinal fluid (CSF) space, in contrast toadministration orally, into the blood stream, into a body cavity or intoa lumen of an organ. Substantially higher dosages can be used in topicaladministration. Actual methods for preparing parenterally administrableformulations will be known or apparent to those skilled in the art andare described in more detail in such publications as Remington's, supra.See also Nieman, In “Receptor Mediated Antisteroid Action,” Agarwal, etal., eds., De Gruyter, New York (1987).

The duration of treatment with nonsteroidal GRMs to reduce the tumorload of NF 2, e.g., meningioma or schwannoma or otherwise ameliorate thesymptoms of these tumors can vary according to the severity of thecondition in a subject and the subject's response to nonsteroidal GRMs.In some embodiments, nonsteroidal GRMs can be administered for a periodof about 1 week to 104 weeks (2 years), more typically about 6 weeks to80 weeks, most typically about 9 to 60 weeks. Suitable periods ofadministration also include 5 to 9 weeks, 5 to 16 weeks, 9 to 16 weeks,16 to 24 weeks, 16 to 32 weeks, 24 to 32 weeks, 24 to 48 weeks, 32 to 48weeks, 32 to 52 weeks, 48 to 52 weeks, 48 to 64 weeks, 52 to 64 weeks,52 to 72 weeks, 64 to 72 weeks, 64 to 80 weeks, 72 to 80 weeks, 72 to 88weeks, 80 to 88 weeks, 80 to 96 weeks, 88 to 96 weeks, and 96 to 104weeks. Suitable periods of administration also include 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 24, 25, 30, 32, 35, 40, 45,48, 50, 52, 55, 60, 64, 65, 68, 70, 72, 75, 80, 85, 88, 90, 95, 96, 100,and 104 weeks. Generally administration of a nonsteroidal GRM should becontinued until clinically significant reduction or amelioration isobserved. Treatment with a nonsteroidal GRM in accordance with themethods disclosed herein may last for as long as two years or evenlonger.

In some embodiments, administration of a nonsteroidal GRM is notcontinuous and can be stopped for one or more periods of time, followedby one or more periods of time where administration resumes. Suitableperiods where administration stops include 5 to 9 weeks, 5 to 16 weeks,9 to 16 weeks, 16 to 24 weeks, 16 to 32 weeks, 24 to 32 weeks, 24 to 48weeks, 32 to 48 weeks, 32 to 52 weeks, 48 to 52 weeks, 48 to 64 weeks,52 to 64 weeks, 52 to 72 weeks, 64 to 72 weeks, 64 to 80 weeks, 72 to 80weeks, 72 to 88 weeks, 80 to 88 weeks, 80 to 96 weeks, 88 to 96 weeks,and 96 to 100 weeks. Suitable periods where administration stops alsoinclude 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 24,25, 30, 32, 35, 40, 45, 48 50, 52, 55, 60, 64, 65, 68, 70, 72, 75, 80,85, 88 90, 95, 96, and 100 weeks.

The dosage regimen also takes into consideration pharmacokineticsparameters well known in the art, i.e., the rate of absorption,bioavailability, metabolism, clearance, and the like (see, e.g.,Hidalgo-Aragones (1996) J. Steroid Biochem. Mol. Biol. 58:611-617;Groning (1996) Pharmazie 51:337-341; Fotherby (1996) Contraception54:59-69; Johnson (1995) J. Pharm. Sci. 84:1144-1146; Rohatagi (1995)Pharmazie 50:610-613; Brophy (1983) Eur. J. Clin. Pharmacol. 24:103-108;the latest Remington's, supra). The state of the art allows theclinician to determine the dosage regimen for each individual patient,GR modulator and disease or condition treated.

Nonsteroidal GRMs can be used in combination with other active agentsknown to be useful in modulating a glucocorticoid receptor, or withadjunctive agents that may not be effective alone, but may contribute tothe efficacy of the active agent.

In some embodiments, co-administration includes administering one activeagent, a nonsteroidal GRM, within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or24 hours of a second active agent. Co-administration includesadministering two active agents simultaneously, approximatelysimultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes ofeach other), or sequentially in any order. In some embodiments,co-administration can be accomplished by co-formulation, i.e., preparinga single pharmaceutical composition including both active agents. Inother embodiments, the active agents can be formulated separately. Inanother embodiment, the active and/or adjunctive agents may be linked orconjugated to one another.

After a pharmaceutical composition including a GRM has been formulatedin an acceptable carrier, it can be placed in an appropriate containerand labeled for treatment of an indicated condition. For administrationof a nonsteroidal GRM, such labeling would include, e.g., instructionsconcerning the amount, frequency and method of administration.

The pharmaceutical compositions useful in the practice of the methodsdisclosed herein can be provided as a salt and can be formed with manyacids, including but not limited to hydrochloric, sulfuric, acetic,lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble inaqueous or other protonic solvents that are the corresponding free baseforms. In other cases, the preparation may be a lyophilized powder in 1mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitol at a pH range of 4.5to 5.5, that is combined with buffer prior to use.

In another embodiment, compositions useful in the practice of themethods disclosed herein are useful for parenteral administration, suchas intravenous (IV) administration or administration into a body cavityor lumen of an organ. The formulations for administration will commonlycomprise a solution of the compositions useful in the practice of themethods disclosed herein dissolved in a pharmaceutically acceptablecarrier. Among the acceptable vehicles and solvents that can be employedare water and Ringer's solution, an isotonic sodium chloride. Inaddition, sterile fixed oils can conventionally be employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid can likewise be used in the preparation ofinjectables. These solutions are sterile and generally free ofundesirable matter. These formulations may be sterilized byconventional, well known sterilization techniques. The formulations maycontain pharmaceutically acceptable auxiliary substances as required toapproximate physiological conditions such as pH adjusting and bufferingagents, toxicity adjusting agents, e.g., sodium acetate, sodiumchloride, potassium chloride, calcium chloride, sodium lactate and thelike. The concentration of the compositions useful in the practice ofthe methods disclosed herein in these formulations can vary widely, andwill be selected primarily based on fluid volumes, viscosities, bodyweight, and the like, in accordance with the particular mode ofadministration selected and the patient's needs. For IV administration,the formulation can be a sterile injectable preparation, such as asterile injectable aqueous or oleaginous suspension. This suspension canbe formulated according to the known art using those suitable dispersingor wetting agents and suspending agents. The sterile injectablepreparation can also be a sterile injectable solution or suspension in anontoxic parenterally-acceptable diluent or solvent, such as a solutionof 1,3-butanediol.

H. Combination Therapies

Also included in the methods disclosed herein are combination therapiesfor treating NF 2, e.g., meningioma or schwannoma, comprising a SGRM andone more conventional cancer therapies, such as, chemical or radiationbased treatments, other therapeutic agents, and surgery, as thosedisclosed in US2011269728, the relevant disclosure is hereinincorporated by reference in its entirety. Non-limiting examples ofchemotherapies include temozolamide, cisplatin (CDDP), carboplatin,procarbazine, mechlorethamine, cyclophosphamide, camptothecin,ifosfamide, melphalan, chlorambucil, busulfan, nitrosurea, dactinomycin,daunorubicin, doxorubicin, bleomycin, plicomycin, mitomycin, etoposide(VP16), tamoxifen, raloxifene, estrogen receptor binding agents, taxol,gemcitabine, navelbine, farnesylprotein, transferase inhibitors,transplatinum, 5-fluorouracil, vincristin, vinblastin and methotrexate,or any analog or derivative variant of the foregoing. In someembodiments the chemotherapy agent is a composition comprisingnanoparticles comprising a thiocolchicine derivative and a carrierprotein (such as albumin). In further embodiments a combination ofchemotherapeutic agents is administered to tumor cells. Thechemotherapeutic agents may be administered serially (within minutes,hours, or days of each other) or in parallel; they also may beadministered to the patient in a premixed single composition.Non-limiting examples of radiation therapies include Y-rays and x-rays.

Suitable therapeutic agents include, for example, vinca alkaloids,agents that disrupt microtubule formation (such as colchicines and itsderivatives), anti-angiogenic agents, e.g. anti-VEGF antibodies (such asbevacizumab), therapeutic antibodies, EGFR targeting agents, tyrosinekinase targeting agent (such as tyrosine kinase inhibitors), serinekinase targeting agents, transitional metal complexes, proteasomeinhibitors, antimetabolites (such as nucleoside analogs), alkylatingagents, platinum-based agents, anthracycline antibiotics, topoisomeraseinhibitors, macrolides, therapeutic antibodies, retinoids (such asalltrans retinoic acids or a derivatives thereof); geldanamycin or aderivative thereof (such as 17-AAG), and other standard chemotherapeuticagents well recognized in the art. As one embodiment, the methodsdisclosed herein expressly proviso out the combination of SGRM andsomatostatin or its derivatives from the methods disclosed herein.

Various combinations with a SGRM and an anticancer agent or compound (ora combination of such agents and compounds) may be employed to reducethe tumor load in the patient. The SGRM and the anticancer agent orcompound can be administered following the same or different dosingregimen. In some embodiments, the SGRM and the anticancer agent orcompound is administered sequentially in any order during the entire orportions of the treatment period. In some embodiments, the SGRM and theanticancer agent is administered simultaneously or approximatelysimultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes ofeach other). Non-limiting examples of combination therapies are asfollows, with administration of the SGRM and the anticancer agent forexample, SGRM is “A” and the anticancer agent or compound, given as partof an anticancer therapy regime, is “B”:

A/B/AB/A/BB/B/AA/A/BA/B/BB/A/AA/B/B/B B/A/B/B B/B/B/A B/B/A/B A/A/B/BA/B/A/B A/B/B/A B/B/A/A B/A/B/A B/A/A/B A/A/A/B B/A/A/A A/B/A/A A/A/B/A

Administration of the therapeutic compounds or agents to a patient willfollow general protocols for the administration of such compounds,taking into account the toxicity, if any, of the therapy. Surgicalintervention may also be applied in combination with the describedtherapy.

I. Evaluate Improvements in Reducing Tumor Loads

The SGRM therapy disclosed herein can reduce the tumor load and conferbeneficial clinical outcome to patients having NF 2, e.g., meningioma orschwannoma. Methods for measuring these responses are well-known toskilled artisans in the field of cancer therapy, e.g., as described inthe Response Evaluation Criteria in Solid Tumors (“RECIST”) guidelines,as described in the PDF named“protocolDevelopment/docs/recist_guideline.pdf” available atetep.cancer.gov, and in the “Endpoints: How the Results of ClinicalTrials are Measured” html article available at www.cancerguide.org.

In one approach, the tumor load is measured by assaying expression oftumor-specific genetic markers. This approach is especially useful formetastatic tumors. A tumor-specific genetic marker is a protein or othermolecule that is unique to cancer cells or is much more abundant in themas compared to non-cancer cells. Useful tumor biomarkers for schwannomaare known, for example, VEGF and those described in Toren et al., HumanGenomics 2014 (8): 10. Useful tumor biomarkers for meningitis are alsoknown, for example, those described in Stuart et al., J. Neurol.70(1):10 (2011).

Methods of measuring the expression levels of a tumor-specific geneticmarker are well known. In some embodiments, mRNA of the genentic markeris isolated from the blood sample or a tumor tissue and real-timereverse transcriptase-polymerase chain reaction (RT-PCR) is performed toquantify expression of the genetic marker. In some embodiments, westernblots or immunohistochemistry analysis are performed to evaluate theprotein expression of the tumor-specific genetic marker. Typically thelevels of the tumor-specific genetic marker are measured in multiplesamples taken over time of the combination therapy methods disclosedherein, and a decrease in levels correlates with a reduction in tumorload.

In another approach, the reduction of tumor load by the combinationtherapy disclosed herein is shown by a reduction in tumor size or areduction of amount of cancer in the body. Measuring tumor size istypically achieved by imaging-based techniques. For example, computedtomography (CT) scan can provide accurate and reliable anatomicinformation about not only tumor shrinkage or growth but alsoprogression of disease by identifying either growth in existing lesionsor the development of new lesions or tumor metastasis.

In yet another approach, a reduction of tumor load can be assessed byfunctional and metabolic imaging techniques. These techniques canprovide earlier assessment of therapy response by observing alterationsin perfusion, oxygenation and metabolism. For example, ¹⁸F-FDG PET usesradiolabelled glucose analogue molecules to assess tissue metabolism.Tumors typically have an elevated uptake of glucose, a change in valuecorresponding to a decrease in tumor tissue metabolism indicates areduction in tumor load. Similar imaging techniques are disclosed inKang et al., Korean J. Radiol. (2012) 13(4) 371-390.

A patient receiving the therapy disclosed herein may exhibit varyingdegrees of tumor load reduction. In some cases, a patient can exhibit aComplete Response (CR), also referred to as “no evidence of disease(NED)”. CR means all detectable tumor has disappeared as indicated bytests, physical exams and scans. In some cases, a patient receiving thecombination therapy disclosed herein can experience a Partial Response(PR), which roughly corresponds to at least a 50% decrease in the totaltumor volume but with evidence of some residual disease still remaining.In some cases the residual disease in a deep partial response mayactually be dead tumor or scar so that a few patients classified ashaving a PR may actually have a CR. Also many patients who showshrinkage during treatment show further shrinkage with continuedtreatment and may achieve a CR. In some cases, a patient receiving thecombination therapy can experience a Minor Response (MR), which roughlymeans a small amount of shrinkage that is more than 25% of total tumorvolume but less than the 50% that would make it a PR. In some cases, apatient receiving the combination therapy can exhibit Stable Disease(SD), which means the tumors stay roughly the same size, but can includeeither a small amount of growth (typically less than 20 or 25%) or asmall amount of shrinkage (Anything less than a PR unless minorresponses are broken out. If so, then SD is defined as typically less25%).

Desired beneficial or desired clinical results from the combinationtherapy may also include e. g., reduced (i.e., slowing to some extentand/or stop) cancer cell infiltration into peripheral organs; inhibit(i.e., slow to some extent and/or stop) tumor metastasis; increasedresponse rates (RR); increased duration of response; relieved to someextent one or more of the symptoms associated with the cancer; decreaseddose of other medications required to treat the disease; delayedprogression of the disease; and/or prolonged survival of patients and/orimproved quality of life. Methods for evaluating these effects are wellknown and/or disclosed in, e.g., cancerguide.org/endpoints.html andRECIST guidelines, supra.

EXAMPLES Example 1. HEPG2 Tyrosine Aminotransferase (TAT) Assay

The following protocol describes an assay for measuring induction of TATby dexamethasone in HepG2 cells (a human liver hepatocellular carcinomacell line; ECACC, UK). HepG2 cells are cultured using MEME mediasupplemented with 10% (v/v) foetal bovine serum; 2 mM L-glutamine and 1%(v/v) NEAA at 37° C., 5%/95% (v/v) CO₂/air. The HepG2 cells are then becounted and adjusted to yield a density of 0.125×10⁶ cells/ml in RPMI1640 without phenol red, 10% (v/v) charcoal stripped FBS, 2 mML-glutamine and seeded at 25,000 cells/well in 200 μl into 96 well,sterile, tissue culture micro titre plates, and incubated at 37° C., 5%CO₂ for 24 hours.

Growth media are then removed and replaced with assay media {RPMI 1640without phenol red, 2 mM L-glutamine+10 μM forskolin}. Test compoundsare then be screened against a challenge of 100 nM dexamethasone.Compounds are then be serially half log diluted in 100% (v/v)dimethylsulfoxide from a 10 mM stock. Then an 8-point half-log dilutioncurve are generated followed by a 1:100 dilution into assay media togive a 10× final assay of the compound concentration, this results infinal assay of the compound concentration that ranged 10 to 0.003 μM in0.1% (v/v) dimethylsulfoxide.

Test compounds are pre-incubated with cells in micro-titre plates for 30minutes at 37° C., 5/95 (v/v) CO₂/air, before the addition of 100 nMdexamethasone and then subsequently for 20 hours to allow optimal TATinduction.

HepG2 cells are then lysed with 30 μl of cell lysis buffer containing aprotease inhibitor cocktail for 15 minutes at 4° C. 155 μl of substratemixture can then be added containing 5.4 mM Tyrosine sodium salt, 10.8mM alpha ketoglutarate and 0.06 mM pyridoxal 5′ phosphate in 0.1Mpotassium phosphate buffer (pH 7.4). After 2 hours incubation at 37° C.the reaction can be terminated by the addition of 15 μl of 10M aqueouspotassium hydroxide solution, and the plates incubated for a further 30minutes at 37° C. The TAT activity product can be measured by absorbanceat λ 340 nm.

Half-maximal inhibition concentration (IC₅₀) values can be calculated byplotting % inhibition (normalised to 100 nM dexamethasone TATstimulation) v. compound concentration and fitting the data to a 4parameter logistic equation. IC₅₀ values can converted to Ki(equilibrium dissociation constant) using the Cheng and Prusoffequation, assuming the antagonists were competitive inhibitors withrespect to dexamethasone.

Example 2. Inhibition of Glioblastoma Cell Growth with SGRM

The effect of GRMs on the growth in culture of human and mouseglioblastoma cells was examined. The GRMs mifepristone and CORT125134inhibited growth in culture of each of five different glioblastoma celllines. The highest drug concentration tested was 50 μM. The cell linesused were the Standard Serum Human glioblastoma (GBM) Cell lines: U251,GL261, U87, and the patient-derived neurosphere cell lines GBM8 andGBM4. Cells were plated at cell numbers of 2000 cells/well, in a 96-wellformat; the experiments were done in triplicate. Cell growth inhibitionby the applied drugs was assayed. Cell growth inhibition was quantifiedby the Alamar Blue method using a commercial assay kit. Cell growthinhibition was determined (“read out”) after 72 hours of treatment. Thehalf-maximal inhibition concentration (IC₅₀) values determined formifepristone ranged from about 16 micromolar (μM) to about 24 μM. TheIC₅₀ values determined for CORT125134 ranged from about 5 μM to about 29μM.

Cell Cultures:

The human glioblastoma cell lines (obtained from the American TypeCulture Collection (ATCC), Manassas Va., USA) tested were U251 and U87(human), and GL261 (mouse). These were grown as an adherent monolayercultured in DMEM supplemented with 10% fetal bovine serum (FBS)(Seradigm, a subsidiary of VWR, Radnor Pa., USA) and 1% glutaminepen-strep (Omega Scientific, Tarzana Calif., USA). GBM8 (passage 12) andGBM4 are patient derived glioma stem cell lines obtained and cultured asneurospheres (spheroids) as described by Galli et al., “Isolation andcharacterization of tumorigenic, stem-like neural precursors from humanglioblastoma” Cancer Res 2004, 64 (19), 7011-21 and Lee et al., “Tumorstem cells derived from glioblastomas cultured in bFGF and EGF moreclosely mirror the phenotype and genotype of primary tumors than doserum-cultured cell lines” Cancer Cell 2006, 9 (5), 391-403. Initial GBMsurgical samples were dissociated in stem cell isolation mediumcontaining human recombinant EGF (20 ng/μl), human bFGF (10 ng/μl) andheparin (2 μg/ml), washed, filtered through a 30 μm mesh and plated ontoultra-low adherence flasks at a concentration of 5×10⁵ to 1.5×10⁶ viablecells/ml. Sphere cultures were passaged by dissociation, washing andresuspension in neural stem cell culture medium (NeuroCult™ NS-AProliferation kit #05751, Stemcell Technologies, Vancouver, BC, CA),according to the manufacturer's instructions.

Cell Viability Assay:

Cells were seeded into 96-well plates at a density of 2000 cells perwell. Compounds were added 24 hours after the seeding of cells. Allcompounds were diluted in 1% FBS/DMEM. The control was treated withmedia alone. After 3 days incubation (37° C./5% CO₂) Alamar Blue (#BUF012B, AbDSerotec, Kidlington, UK) was added according to themanufacturer's protocol, directly to the medium and placed back in thetissue culture incubator (37° C. 5% CO₂). After 3-18 hours fluorescentsignal was read at 544 ex/590 cm (SpectraMax i3x plate reader, MolecularDevices, San Jose Calif., USA) to determine the number of viable cells.The IC₅₀ values were calculated using commercial software (Prism 5Software, GraphPad, La Jolla Calif., USA).

After 24 hours post incubation, cells were treated with drugs at variousconcentrations for 72 hours. Cell viability was measured after 72 hoursby Alamar Blue and results reported as triplicate experiment. Thefollowing Table presents the IC₅₀ values as determined in theseexperiments.

TABLE Effects of Mifepristone and CORT 125134 on Standard GBM andNeurosphere GBM lines Cell Growth Inhibition (IC₅₀ μM) Cell LineCompound GL261 U87 U251 GBM4 GBM8 Mifepristone 15.74 18.4 18.4 24.1023.96 CORT125134 5.86 5.42 12.5 20.68 29.07

Example 3. Treating a Meningioma Patient with SGRM

A 52-year-old female patient complains of tinnitus and right-sidedhearing loss for 6 months. The enhanced axial T1-weighted MRI of theposterior fossa shows a 16-×11-×18 mm large, heterogeneous, sessilelesion, which extends into her internal auditory canal. She is treatedwith CORT125134 at a dose of 200 mg once a day for eight weeks. Hertumor load is monitored using enhanced MRI before, during and after thetreatment. The imaging results indicate that the size of the tumor isdecreased as compared to the tumor size before treatment baseline, andthe reduction is more than 50% at the end of the treatment period.

Example 4. Treating a Meningioma Patient with SGRM

A 52-year-old female patient complains of tinnitus and right-sidedhearing loss for 6 months. The enhanced axial T1-weighted MRI of theposterior fossa shows a 16-×11-×18 mm large, heterogeneous, sessilelesion, which extends into her internal auditory canal. She is treatedwith CORT125281 at a dose of 200 mg once a day for eight weeks. Hertumor load is monitored using enhanced MRI before, during and after thetreatment. The imaging results indicate that the size of the tumor isdecreased as compared to baseline, and the reduction is more than 50% atthe end of the treatment period.

All patents, patent publications, and all other publications citedherein are hereby incorporated by reference herein in their entiretiesfor all purposes.

What is claimed is:
 1. A method of treating a GR⁺ neuroepithelial tumorin a subject, the method comprising administering to the subject aselective glucocorticoid receptor modulator (SGRM) in an amounteffective to reduce the tumor load of the neuroepithelial tumor in thepatient with the proviso that the subject not be otherwise sufferingfrom a disorder treatable with SGRM, nor does the tumor secreteadrenocorticotropic hormone (ACTH).
 2. The method of claim 1, whereinthe GR⁺ neuroepithelial tumor is neurofibromatosis type
 2. 3. The methodof claim 1, wherein the GR⁺ neuroepithelial tumor is selected from thegroup consisting of schwannoma, meningioma, and ependymoma.
 4. Themethod of claim 1, wherein the method comprises administering the SGRMfor at least two weeks.
 5. The method of claim 1, wherein the effectiveamount is a daily dose of between 1 and 100 mg/kg/day, wherein the SGRMis administered alone or with at least one non-SGRM therapy, wherein theat least one non-SGRM therapy is a chemotherapy, a radiation therapy orother therapeutic agents.
 6. The method of claim 1, wherein the dailydose is 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 30, 40, 50 60, 70, 80, 90or 100 mg/kg/day.
 7. The method of claim 1, wherein the nonsteroidalglucocorticoid receptor modulator is administrated for at least 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30,35, 40, 45, 50, 55, 60, 65, 70, 75, or 80 weeks.
 8. The method of any ofthe claims 1-7, wherein the glucocorticoid receptor modulator comprisesa steroidal backbone with at least one phenyl-containing moiety in the11-β position of the steroidal backbone.
 9. The method of claim 8,wherein the phenyl-containing moiety in the 11-β position of thesteroidal backbone is a dimethylaminophenyl moiety.
 10. The method ofclaim 8, wherein the glucocorticoid receptor modulator is mifepristone.11. The method of any of the claims 1-7, wherein the glucocorticoidreceptor modulator is selected from the group consisting of11β-(4-dimethylaminoethoxyphenyl)-17α-propynyl-17β-hydroxy-4,9estradien-3-one and(17α)-17-hydroxy-19-(4-methylphenyl)androsta-4,9(11)-dien-3-one.
 12. Themethod of any of the claims 1-7, wherein the glucocorticoid receptormodulator is(11β,17β)-11-(1,3-benzodioxol-5-yl)-17-hydroxy-7-(1-propynyl)estra-4,9-dien-3-one.13. The method of any of the claims 1-7, wherein the glucocorticoidreceptor modulator has a non-steroidal backbone.
 14. The method of claim13, wherein the glucocorticoid receptor modulator backbone is acyclohexyl pyrimidine.
 15. The method of claim 14, wherein thecyclohexyl pyrimidine has the following formula:

wherein the dashed line is absent or a bond; X is selected from thegroup consisting of O and S; R¹ is selected from the group consisting ofcycloalkyl, heterocycloalkyl, aryl and heteroaryl, optionallysubstituted with from 1 to 3 R^(1a) groups; each R^(1a) is independentlyselected from the group consisting of H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkyl OR^(1b), halogen, C₁₋₆ haloalkyl, C₁₋₆haloaloxy, OR^(1b), NR^(1b)R^(1c), C(O)R^(1b), C(O)OR^(1b), OC(O)R^(1b),C(O)NR^(1b)R^(1c), NR^(1b)C(O)R^(1c), SO₂R^(1b), SO₂NR^(1b)R^(1c),cycloalkyl, heterocycloalkyl, aryl and heteroaryl; R^(1b) and R^(1c) areeach independently selected from the group consisting of H and C₁₋₆alkyl; R² is selected from the group consisting of H, C₁₋₆ alkyl, C₁₋₆alkyl-OR^(1b), C₁₋₆ alkyl NR^(1b)R^(1c) and C₁₋₆ alkyleneheterocycloalkyl; R³ is selected from the group consisting of H and C₁₋₆alkyl; Ar is aryl, optionally substituted with 1-4 R⁴ groups; each R⁴ isindependently selected from the group consisting of H, C₁₋₆ alkyl, C₁₋₆alkoxy, halogen, C₁₋₆ haloalkyl and C₁₋₆ haloalkoxy; L¹ is a bond orC₁₋₆ alkylene; and subscript n is an integer from 0 to 3, or salts andisomers thereof.
 16. The method of claim 14, wherein the cyclohexylpyrimidine has the following formula:


17. The method of claim 13, wherein the glucocorticoid receptormodulator backbone is a fused azadecalin.
 18. The method of claim 17,wherein the fused azadecalin is a compound having the following formula:

wherein L¹ and L² are members independently selected from a bond andunsubstituted alkylene; R¹ is a member selected from unsubstitutedalkyl, unsubstituted heteroalkyl, unsubstituted heterocycloalkyl,—OR^(1A), NR^(1C)R^(1D), —C(O)NR^(1C)R^(1D), and —C(O)OR^(1A), whereinR^(1A) is a member selected from hydrogen, unsubstituted alkyl andunsubstituted heteroalkyl, R^(1C) and R^(1D) are members independentlyselected from unsubstituted alkyl and unsubstituted heteroalkyl, whereinR^(1C) and R^(1D) are optionally joined to form an unsubstituted ringwith the nitrogen to which they are attached, wherein said ringoptionally comprises an additional ring nitrogen; R² has the formula:

wherein R^(2G) is a member selected from hydrogen, halogen,unsubstituted alkyl, unsubstituted heteroalkyl, unsubstitutedcycloalkyl, unsubstituted heterocycloalkyl, —CN, and —CF₃; J is phenyl;t is an integer from 0 to 5; X is —S(O₂)—; and R⁵ is phenyl optionallysubstituted with 1-5 R^(5A) groups, wherein R^(5A) is a member selectedfrom hydrogen, halogen, —OR^(5A1), S(O₂)NR^(5A2)R^(5A3), —CN, andunsubstituted alkyl, wherein R^(5A1) is a member selected from hydrogenand unsubstituted alkyl, and R^(5A2) and R^(5A3) are membersindependently selected from hydrogen and unsubstituted alkyl, or saltsand isomers thereof.
 19. The method of claim 17, wherein the fusedazadecalin is:


20. The method of claim 13, wherein the glucocorticoid receptormodulator backbone is a heteroaryl ketone fused azadecalin or anoctahydro fused azadecalin.
 21. The method of claim 20, wherein theheteroaryl ketone fused azadecalin has the formula:

wherein R¹ is a heteroaryl ring having from 5 to 6 ring members and from1 to 4 heteroatoms each independently selected from the group consistingof N, O and S, optionally substituted with 1-4 groups each independentlyselected from R^(1a); each R^(1a) is independently selected from thegroup consisting of hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, CN, N-oxide, C₃₋₈ cycloalkyl, and C₃₋₈heterocycloalkyl; ring J is selected from the group consisting of acycloalkyl ring, a heterocycloalkyl ring, an aryl ring and a heteroarylring, wherein the heterocycloalkyl and heteroaryl rings have from 5 to 6ring members and from 1 to 4 heteroatoms each independently selectedfrom the group consisting of N, O and S; each R² is independentlyselected from the group consisting of hydrogen, C₁₋₆ alkyl, halogen, C₁₆ haloalkyl, C₁ ₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkyl-C₁₋₆ alkoxy, CN,OH, NR^(2a)R^(2b), C(O)R^(2a), C(O)OR^(2a), C(O)NR^(2a)R^(2b), SR^(2a),S(O)R^(2a), S(O)₂R^(2a), C₃₋₈ cycloalkyl, and C₃₋₈ heterocycloalkyl,wherein the heterocycloalkyl groups are optionally substituted with 1-4R^(2c) groups; alternatively, two R² groups linked to the same carbonare combined to form an oxo group (═O); alternatively, two R² groups arecombined to form a heterocycloalkyl ring having from 5 to 6 ring membersand from 1 to 3 heteroatoms each independently selected from the groupconsisting of N, O and S, wherein the heterocycloalkyl ring isoptionally substituted with from 1 to 3 R^(2d) groups; R^(2a) and R^(2b)are each independently selected from the group consisting of hydrogenand C₁₋₆ alkyl; each R^(2c) is independently selected from the groupconsisting of hydrogen, halogen, hydroxy, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,CN, and NR^(2a)R^(2b); each R^(2d) is independently selected from thegroup consisting of hydrogen and C₁₋₆ alkyl, or two R^(2d) groupsattached to the same ring atom are combined to form (═O); R³ is selectedfrom the group consisting of phenyl and pyridyl, each optionallysubstituted with 1-4 R^(3a) groups; each R^(3a) is independentlyselected from the group consisting of hydrogen, halogen, and C₁₋₆haloalkyl; and subscript n is an integer from 0 to 3; or salts andisomers thereof.
 22. The method of claim 20, wherein theheteroaryl-ketone fused azadecalin is selected from the group consistingof:


23. The method of claim 20, wherein the octahydro fused azadecalin hasthe formula:

wherein R¹ is a heteroaryl ring having from 5 to 6 ring members and from1 to 4 heteroatoms each independently selected from the group consistingof N, O and S, optionally substituted with 1-4 groups each independentlyselected from R^(1a); each R^(1a) is independently selected from thegroup consisting of hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, N-oxide, and C₃₋₈ cycloalkyl; ring J isselected from the group consisting of an aryl ring and a heteroaryl ringhaving from 5 to 6 ring members and from 1 to 4 heteroatoms eachindependently selected from the group consisting of N, O and S; each R²is independently selected from the group consisting of hydrogen, C₁₋₆alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆alkyl-C₁₋₆ alkoxy, CN, OH, NR^(2a)R^(2b), C(O)R^(2a), C(O)OR^(2a),C(O)NR^(2a)R^(2b), SR^(2a), S(O)R^(2a), S(O)₂R^(2a), C₃₋₈ cycloalkyl,and C₃₋₈ heterocycloalkyl having from 1 to 3 heteroatoms eachindependently selected from the group consisting of N, O and S;alternatively, two R² groups on adjacent ring atoms are combined to forma heterocycloalkyl ring having from 5 to 6 ring members and from 1 to 3heteroatoms each independently selected from the group consisting of N,O and S, wherein the heterocycloalkyl ring is optionally substitutedwith from 1 to 3 R^(2c) groups; R^(2a), R^(2b) and R^(2c) are eachindependently selected from the group consisting of hydrogen and C₁₋₆alkyl; each R^(3a) is independently halogen; and subscript n is aninteger from 0 to 3, or salts and isomers thereof.
 24. The method ofclaim 20, wherein the octahydro fused azadecalin has the formula:


25. The method of claim 10, wherein the tumor is a schwannoma.
 26. Themethod of any of the claims 1-7, wherein the SGRM is CORT125134 orCORT125281.
 27. A method of treating a schwannoma or meningioma in apatient, the method comprising administering to the subject a selectiveglucocorticoid receptor modulator (SGRA) in an amount effective toreduce the tumor load of schwannoma or meningioma in the patient. 28.The method of claim 27, wherein the method comprises administering theSGRM for at least two weeks.
 29. The method of claim 27, wherein theeffective amount is a daily dose of between 1 and 100 mg/kg/day.
 30. Themethod of claim 27, wherein the daily dose is 1, 2, 4, 6, 8, 10, 12, 14,16, 18, 20, 30, 40, 50 60, 70, 80, 90 or 100 mg/kg/day.
 31. The methodof claim 27, wherein the nonsteroidal glucocorticoid receptor modulatoris administrated for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75,or 80 weeks.
 32. The method of claim 27, wherein the glucocorticoidreceptor antagonist comprises a steroidal backbone with at least onephenyl-containing moiety in the 11-β position of the steroidal backbone.33. The method of claim 32, wherein the phenyl-containing moiety in the11-β position of the steroidal backbone is a dimethylaminophenyl moiety.34. The method of claim 32, wherein the glucocorticoid receptorantagonist is mifepristone.
 35. The method of claim 27, wherein theglucocorticoid receptor antagonist is selected from the group consistingof 11β-(4-dimethylaminoethoxyphenyl)-17α-propynyl-17β-hydroxy-4,9estradien-3-one and(17α)-17-hydroxy-19-(4-methylphenyl)androsta-4,9(11)-dien-3-one.
 36. Themethod of claim 27, wherein the glucocorticoid receptor antagonist is(11β,17β)-11-(1,3-benzodioxol-5-yl)-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one.37. The method of claim 27, wherein the glucocorticoid receptorantagonist has a non-steroidal backbone.
 38. The method of claim 37,wherein the glucocorticoid receptor antagonist backbone is a cyclohexylpyrimidine.
 39. The method of claim 38, wherein the cyclohexylpyrimidine has the following formula:

wherein the dashed line is absent or a bond; X is selected from thegroup consisting of O and S; R¹ is selected from the group consisting ofcycloalkyl, heterocycloalkyl, aryl and heteroaryl, optionallysubstituted with from 1 to 3 R^(1a) groups; each R^(1a) is independentlyselected from the group consisting of H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkyl OR^(1b), halogen, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, OR^(1b), NR^(1b)R^(1c), C(O)R^(1b), C(O)OR^(1b),OC(O)R^(1b), C(O)NR^(1b)R^(1c), NR^(1b)C(O)R^(1c), SO₂R^(1b),SO₂NR^(1b)R^(1c), cycloalkyl, heterocycloalkyl, aryl and heteroaryl;R^(1b) and R^(1c) are each independently selected from the groupconsisting of H and C₁₋₆ alkyl; R² is selected from the group consistingof H, C₁₋₆ alkyl, C₁₋₆ alkyl-OR^(1b), C₁₋₆ alkyl NR^(1b)R^(1c) and C₁₋₆alkylene heterocycloalkyl; R³ is selected from the group consisting of Hand C₁₋₆ alkyl; Ar is aryl, optionally substituted with 1-4 R⁴ groups;each R⁴ is independently selected from the group consisting of H, C₁₋₆alkyl, C₁₋₆ alkoxy, halogen, C₁₋₆ haloalkyl and C₁₋₆ haloalkoxy; L¹ is abond or C₁₋₆ alkylene; and subscript n is an integer from 0 to 3, orsalts and isomers thereof.
 40. The method of claim 38, wherein thecyclohexyl pyrimidine has the following formula:


41. The method of claim 37, wherein the glucocorticoid receptorantagonist backbone is a fused azadecalin.
 42. The method of claim 41,wherein the fused azadecalin is a compound having the following formula:

wherein L¹ and L² are members independently selected from a bond andunsubstituted alkylene; R¹ is a member selected from unsubstitutedalkyl, unsubstituted heteroalkyl, unsubstituted heterocycloalkyl,—OR^(1A), NR^(1C)R^(1D), —C(O)NR^(1C)R^(1D), and —C(O)OR^(1A), whereinR^(1A) is a member selected from hydrogen, unsubstituted alkyl andunsubstituted heteroalkyl, R^(1C) and R^(1D) are members independentlyselected from unsubstituted alkyl and unsubstituted heteroalkyl, whereinR^(1C) and R^(1D) are optionally joined to form an unsubstituted ringwith the nitrogen to which they are attached, wherein said ringoptionally comprises an additional ring nitrogen; R² has the formula:

wherein R^(2G) is a member selected from hydrogen, halogen,unsubstituted alkyl, unsubstituted heteroalkyl, unsubstitutedcycloalkyl, unsubstituted heterocycloalkyl, —CN, and —CF₃; J is phenyl;t is an integer from 0 to 5; X is —S(O₂)—; and R⁵ is phenyl optionallysubstituted with 1-5 R^(5A) groups, wherein R^(5A) is a member selectedfrom hydrogen, halogen, —OR^(5A1), S(O₂)NR^(5A2)R^(5A3), —CN, andunsubstituted alkyl, wherein R^(5A1) is a member selected from hydrogenand unsubstituted alkyl, and R^(5A2) and R^(5A3) are membersindependently selected from hydrogen and unsubstituted alkyl, or saltsand isomers thereof.
 43. The method of claim 41, wherein the fusedazadecalin is:


44. The method of claim 37, wherein the glucocorticoid receptorantagonist backbone is a heteroaryl ketone fused azadecalin or anoctahydro fused azadecalin.
 45. The method of claim 44, wherein theheteroaryl ketone fused azadecalin has the formula:

wherein R¹ is a heteroaryl ring having from 5 to 6 ring members and from1 to 4 heteroatoms each independently selected from the group consistingof N, O and S, optionally substituted with 1-4 groups each independentlyselected from R^(1a); each R^(1a) is independently selected from thegroup consisting of hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, CN, N-oxide, C₃₋₈ cycloalkyl, and C₃₋₈heterocycloalkyl; ring J is selected from the group consisting of acycloalkyl ring, a heterocycloalkyl ring, an aryl ring and a heteroarylring, wherein the heterocycloalkyl and heteroaryl rings have from 5 to 6ring members and from 1 to 4 heteroatoms each independently selectedfrom the group consisting of N, O and S; each R² is independentlyselected from the group consisting of hydrogen, C₁₋₆ alkyl, halogen, C₁₆ haloalkyl, C₁ ₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkyl-C₁₋₆ alkoxy, CN,OH, NR^(2a)R^(2b), C(O)R^(2a), C(O)OR^(2a), C(O)NR^(2a)R^(2b), SR^(2a),S(O)R^(2a), S(O)₂R^(2a), C₃₋₈ cycloalkyl, and C₃₋₈ heterocycloalkyl,wherein the heterocycloalkyl groups are optionally substituted with 1-4R^(2c) groups; alternatively, two R² groups linked to the same carbonare combined to form an oxo group (═O); alternatively, two R² groups arecombined to form a heterocycloalkyl ring having from 5 to 6 ring membersand from 1 to 3 heteroatoms each independently selected from the groupconsisting of N, O and S, wherein the heterocycloalkyl ring isoptionally substituted with from 1 to 3 R^(2d) groups; R^(2a) and R^(2b)are each independently selected from the group consisting of hydrogenand C₁₋₆ alkyl; each R^(2c) is independently selected from the groupconsisting of hydrogen, halogen, hydroxy, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,CN, and NR^(2a)R^(2b); each R^(2d) is independently selected from thegroup consisting of hydrogen and C₁₋₆ alkyl, or two R^(2d) groupsattached to the same ring atom are combined to form (═O); R³ is selectedfrom the group consisting of phenyl and pyridyl, each optionallysubstituted with 1-4 R^(3a) groups; each R^(3a) is independentlyselected from the group consisting of hydrogen, halogen, and C₁₋₆haloalkyl; and subscript n is an integer from 0 to 3; or salts andisomers thereof.
 46. The method of claim 44, wherein theheteroaryl-ketone fused azadecalin is selected from the group consistingof:


47. The method of claim 44, wherein the octahydro fused azadecalin hasthe formula:

wherein R¹ is a heteroaryl ring having from 5 to 6 ring members and from1 to 4 heteroatoms each independently selected from the group consistingof N, O and S, optionally substituted with 1-4 groups each independentlyselected from R^(1a); each R^(1a) is independently selected from thegroup consisting of hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, N-oxide, and C₃₋₈ cycloalkyl; ring J isselected from the group consisting of an aryl ring and a heteroaryl ringhaving from 5 to 6 ring members and from 1 to 4 heteroatoms eachindependently selected from the group consisting of N, O and S; each R²is independently selected from the group consisting of hydrogen, C₁₋₆alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆alkyl-C₁₋₆ alkoxy, CN, OH, NR^(2a)R^(2b), C(O)R^(2a), C(O)OR^(2a),C(O)NR^(2a)R^(2b), SR^(2a), S(O)R^(2a), S(O)₂R^(2a), C₃₋₈ cycloalkyl,and C₃₋₈ heterocycloalkyl having from 1 to 3 heteroatoms eachindependently selected from the group consisting of N, O and S;alternatively, two R² groups on adjacent ring atoms are combined to forma heterocycloalkyl ring having from 5 to 6 ring members and from 1 to 3heteroatoms each independently selected from the group consisting of N,O and S, wherein the heterocycloalkyl ring is optionally substitutedwith from 1 to 3 R^(2c) groups; R^(2a), R^(2b) and R^(2c) are eachindependently selected from the group consisting of hydrogen and C₁₋₆alkyl; each R^(3a) is independently halogen; and subscript n is aninteger from 0 to 3, or salts and isomers thereof.
 48. The method ofclaim 44, wherein the octahydro fused azadecalin has the formula:


49. The method of claim 34, wherein the tumor is schwannoma.
 50. Themethod of any of the claims 27-33, wherein the SGRM is CORT125134 orCORT125281.